GLP-1 Receptor Agonists and Uses Thereof

ABSTRACT

Provided herein are 6-carboxylic acids of benzimidazoles and 4-aza-, 5-aza-, and 7-aza-benzimidazoles as GLP-1R agonists, processes to make said compounds, and methods comprising administering said compounds to a mammal in need thereof.

This application is a divisional application of U.S. patent applicationSer. No. 16/436,311 filed Jun. 10, 2019, which in turn claims thebenefit of priority to U.S. Provisional Patent Application Ser. No.62/684,696 filed Jun. 13, 2018, to U.S. Provisional Patent ApplicationSer. No. 62/846,944 filed May 13, 2019, and to U.S. Provisional PatentApplication Ser. No. 62/851,206 filed May 22, 2019, the disclosure ofeach of which is hereby incorporated by reference in its entirety.

FIELD OF INVENTION

Provided herein are 6-carboxylic acids of benzimidazoles and 4-aza-,5-aza-, and 7-aza-benzimidazoles as GLP-1R agonists, processes to makesaid compounds, and methods comprising administering said compounds to amammal in need thereof.

BACKGROUND OF THE INVENTION

Diabetes is a major public health concern because of its increasingprevalence and associated health risks. The disease is characterized byhigh levels of blood glucose resulting from defects in insulinproduction, insulin action, or both. Two major forms of diabetes arerecognized, Type 1 and Type 2. Type 1 diabetes (T1D) develops when thebody's immune system destroys pancreatic beta cells, the only cells inthe body that make the hormone insulin that regulates blood glucose. Tosurvive, people with Type 1 diabetes must have insulin administered byinjection or a pump. Type 2 diabetes mellitus (referred to generally asT2DM) usually begins with either insulin resistance or when there isinsufficient production of insulin to maintain an acceptable glucoselevel.

Currently, various pharmacological approaches are available for treatinghyperglycemia and subsequently, T2DM (Hampp, C. et al. Use ofAntidiabetic Drugs in the U.S., 2003-2012, Diabetes Care 2014, 37,1367-1374). These may be grouped into six major classes, each actingthrough a different primary mechanism: (A) Insulin secretogogues,including sulphonyl-ureas (e.g., glipizide, glimepiride, glyburide),meglitinides (e.g., nateglidine, repaglinide), dipeptidyl peptidase IV(DPP-IV) inhibitors (e.g., sitagliptin, vildagliptin, alogliptin,dutogliptin, linagliptin, saxogliptin), and glucagon-like peptide-1receptor (GLP-1R) agonists (e.g., liraglutide, albiglutide, exenatide,lixisenatide, dulaglutide, semaglutide), which enhance secretion ofinsulin by acting on the pancreatic beta-cells. Sulphonyl-ureas andmeglitinides have limited efficacy and tolerability, cause weight gainand often induce hypoglycemia. DPP-IV inhibitors have limited efficacy.Marketed GLP-1R agonists are peptides administered by subcutaneousinjection. Liraglutide is additionally approved for the treatment ofobesity. (B) Biguanides (e.g., metformin) are thought to act primarilyby decreasing hepatic glucose production. Biguanides often causegastrointestinal disturbances and lactic acidosis, further limitingtheir use. (C) Inhibitors of alpha-glucosidase (e.g., acarbose) decreaseintestinal glucose absorption. These agents often cause gastrointestinaldisturbances. (D) Thiazolidinediones (e.g., pioglitazone, rosiglitazone)act on a specific receptor (peroxisome proliferator-activatedreceptor-gamma) in the liver, muscle and fat tissues. They regulatelipid metabolism subsequently enhancing the response of these tissues tothe actions of insulin. Frequent use of these drugs may lead to weightgain and may induce edema and anemia. (E) Insulin is used in more severecases, either alone or in combination with the above agents, andfrequent use may also lead to weight gain and carries a risk ofhypoglycemia. (F) sodium-glucose linked transporter cotransporter 2(SGLT2) inhibitors (e.g., dapagliflozin, empagliflozin, canagliflozin,ertugliflozin) inhibit reabsorption of glucose in the kidneys andthereby lower glucose levels in the blood. This emerging class of drugsmay be associated with ketoacidosis and urinary tract infections.

However, with the exception of GLP-1R agonists and SGLT2 inhibitors, thedrugs have limited efficacy and do not address the most importantproblems, the declining β-cell function and the associated obesity.

Obesity is a chronic disease that is highly prevalent in modern societyand is associated with numerous medical problems including hypertension,hypercholesterolemia, and coronary heart disease. It is further highlycorrelated with T2DM and insulin resistance, the latter of which isgenerally accompanied by hyperinsulinemia or hyperglycemia, or both. Inaddition, T2DM is associated with a two to fourfold increased risk ofcoronary artery disease. Presently, the only treatment that eliminatesobesity with high efficacy is bariatric surgery, but this treatment iscostly and risky. Pharmacological intervention is generally lessefficacious and associated with side effects. There is therefore anobvious need for more efficacious pharmacological intervention withfewer side effects and convenient administration.

Although T2DM is most commonly associated with hyperglycemia and insulinresistance, other diseases associated with T2DM include hepatic insulinresistance, impaired glucose tolerance, diabetic neuropathy, diabeticnephropathy, diabetic retinopathy, obesity, dyslipidemia, hypertension,hyperinsulinemia and nonalcoholic fatty liver disease (NAFLD).

NAFLD is the hepatic manifestation of metabolic syndrome, and is aspectrum of hepatic conditions encompassing steatosis, non-alcoholicsteatohepatitis (NASH), fibrosis, cirrhosis and ultimatelyhepatocellular carcinoma. NAFLD and NASH are considered the primaryfatty liver diseases as they account for the greatest proportion ofindividuals with elevated hepatic lipids.

The severity of NAFLD/NASH is based on the presence of lipid,inflammatory cell infiltrate, hepatocyte ballooning, and the degree offibrosis. Although not all individuals with steatosis progress to NASH,a substantial portion does.

GLP-1 is a 30 amino acid long incretin hormone secreted by the L-cellsin the intestine in response to ingestion of food. GLP-1 has been shownto stimulate insulin secretion in a physiological and glucose-dependentmanner, decrease glucagon secretion, inhibit gastric emptying, decreaseappetite, and stimulate proliferation of beta-cells. In non-clinicalexperiments GLP-1 promotes continued beta-cell competence by stimulatingtranscription of genes important for glucose-dependent insulin secretionand by promoting beta-cell neogenesis (Meier, et al. Biodrugs. 2003; 17(2): 93-102).

In a healthy individual, GLP-1 plays an important role regulatingpost-prandial blood glucose levels by stimulating glucose-dependentinsulin secretion by the pancreas resulting in increased glucoseabsorption in the periphery. GLP-1 also suppresses glucagon secretion,leading to reduced hepatic glucose output. In addition, GLP-1 delaysgastric emptying and slows small bowel motility delaying foodabsorption. In people with T2DM, the normal post-prandial rise in GLP-1is absent or reduced (Vilsboll T, et al. Diabetes. 2001. 50; 609-613).

Holst (Physiol. Rev. 2007, 87, 1409) and Meier (Nat. Rev. Endocrinol.2012, 8, 728) describe that GLP-1 receptor agonists, such as GLP-1,liraglutide and exendin-4, have 3 major pharmacological activities toimprove glycemic control in patients with T2DM by reducing fasting andpostprandial glucose (FPG and PPG): (i) increased glucose-dependentinsulin secretion (improved first- and second-phase), (ii) glucagonsuppressing activity under hyperglycemic conditions, (iii) delay ofgastric emptying rate resulting in retarded absorption of meal-derivedglucose.

There remains a need for an easily-administered prevention and/ortreatment for cardiometabolic and associated diseases.

BRIEF DESCRIPTION OF FIGURES

FIG. 1 represents an observed powder X-ray diffraction pattern for ananhydrous (anhydrate) crystal form (Form 1) of tris salt of compoundExample 7.

FIG. 2 represents an observed powder X-ray diffraction pattern for ananhydrous (anhydrate) crystal form (Form A) of tris salt of compoundExample 10.

DETAILED DESCRIPTION OF THE INVENTION

The present invention concerns compounds of Formula I

or a pharmaceutically acceptable salt thereof, wherein

R is F, Cl, or —CN;

p is 0 or 1;

Ring A is phenyl or a 6-membered heteroaryl;

m is 0, 1, 2, or 3;

each R¹ is independently selected from halogen, —CN, —C₁₋₃alkyl, and—OC₁₋₃alkyl, wherein the alkyl of C₁₋₃alkyl and OC₁₋₃alkyl issubstituted with 0 to 3 F atoms;

R² is H or —C₁₋₃alkyl, wherein alkyl is substituted with 0 to 1 OH;

each R³ is independently F, —OH, —CN, —C₁₋₃alkyl, —OC₁₋₃alkyl, and—C₃₋₄cycloalkyl, or 2 R³s may together cyclize to form—C₃₋₄spirocycloalkyl, wherein the alkyl of C₁₋₃alkyl and OC₁₋₃alkyl,cycloalkyl, or spirocycloalkyl may be substituted as valency allows with0 to 3 F atoms and with 0 to 1 —OH;

q is 0, 1, or 2;

X-L is N—CH₂, CHCH₂, or cyclopropyl;

Y is CH or N;

R⁴ is —C₁₋₃alkyl, —C₀₋₃alkylene-C₃₋₆cycloalkyl, —C₀₋₃alkylene-R⁵, or—C₁₋₃alkylene-R⁶, wherein said alkyl may be substituted as valencyallows with 0 to 3 substituents independently selected from 0 to 3 Fatoms and 0 to 1 substituent selected

from —C₀₋₁alkylene-CN, —C₀₋₁alkylene-OR^(O), —SO₂—N(R^(N))₂,—C(O)—N(R^(N))₂, —N(C═O)(R^(N)), and —N(R^(N))₂, andwherein said alkylene and cycloalkyl may be independently substituted asvalency allows with 0 to 2 substituents independently selected from 0 to2 F atoms and 0 to 1 substituent selected from —C₀₋₁alkylene-CN,—C₀₋₁alkylene-OR^(O), and —N(R^(N))₂;

R⁵ is a 4- to 6-membered heterocycloalkyl, wherein said heterocycloalkylmay be substituted with 0 to 2 substituents as valency allowsindependently selected from:

-   -   0 to 1 oxo (═O),    -   0 to 1 —CN,    -   0 to 2 F atoms, and    -   0 to 2 substituents independently selected from —C₁₋₃alkyl and        —OC₁₋₃alkyl, wherein the alkyl of C₁₋₃alkyl and OC₁alkyl may be        substituted with 0 to 3 substituents as valency allows        independently selected from:        -   0 to 3 F atoms,        -   0 to 1 —CN, and        -   0 to 1 —OR^(O);

R⁶ is a 5- to 6-membered heteroaryl, wherein said heteroaryl may besubstituted with 0 to 2 substituents as valency allows independentlyselected from:

-   -   0 to 2 halogens,    -   0 to 1 substituent selected from —OR^(O) and —N(R^(N))₂, and    -   0 to 2 —C₁₋₃alkyl, wherein the alkyl may be substituted with 0        to 3 substituents as valency allows independently selected from:        -   0 to 3 F atoms, and        -   0 to 1 —OR^(O);

each R^(O) is independently H, or —C₁₋₃alkyl, wherein C₁₋₃alkyl may besubstituted with 0 to 3 F atoms;

each R^(N) is independently H, or —C₁₋₃alkyl;

Z¹, Z², and Z³ are each —CR^(Z), or

one of Z¹, Z², and Z³ is N and the other two are —CR^(Z); and

each R^(Z) is independently H, F, Cl, or —CH₃.

Another embodiment concerns compounds of Formula II

or a pharmaceutically acceptable salt thereof, wherein

R is F;

p is 0 or 1;

Ring A is phenyl or pyridinyl;

m is 0, 1, or 2;

each R¹ is independently selected from halogen, —CN, —C₁₋₃alkyl, and—OC₁₋₃alkyl, wherein the alkyl of C₁₋₃alkyl and OC₁₋₃alkyl issubstituted with 0 to 3 F atoms;

R² is H or CH₃;

X-L is N—CH₂, or cyclopropyl;

Y is CH or N;

Z³ is —CR^(Z) or N; and

R^(Z) is H, F, Cl, or —CH₃.

Another embodiment concerns compounds of Formula III

or a pharmaceutically acceptable salt thereof, wherein

Ring A is phenyl or pyridinyl;

m is 0, 1, or 2;

each R¹ is independently selected from F, C, and —CN;

R² is H or CH₃; and

Y is CH or N.

Another embodiment concerns compounds of Formula IV

or a pharmaceutically acceptable salt thereof, wherein

m is 0, 1, or 2;

each R¹ is independently selected from F, C, and —CN;

R² is H or CH₃; and

Y is CH or N.

Another embodiment concerns compounds of Formula V

or a pharmaceutically acceptable salt thereof, wherein

m is 0 or 1;

R¹ is F, Cl, or —CN;

R² is H or CH₃; and

Y is CH or N.

Another embodiment concerns compounds of Formula IV or Formula V,wherein the phenyl or pyridinyl of Ring A has one R¹ para substitutedrelative to carbon of said phenyl or pyridinyl attached to the dioxolaneto provide:

or a pharmaceutically acceptable salt thereof, wherein

each R¹ is independently selected from F, Cl, and —CN;

R² is H or CH₃; and

Y is CH or N.

Another embodiment concerns compounds of other embodiments herein, e.g.,compounds of Formulas I, or II, or a pharmaceutically acceptable saltthereof, wherein X-L is N—CH₂; and Y is CH or N. From the embodimentsdescribed herein, in such a case, X is N and L is CH₂.

Another embodiment concerns compounds of other embodiments herein, e.g.,compounds of Formulas I, or II, or a pharmaceutically acceptable saltthereof, wherein X-L is CHCH₂; and Y is N. From the embodimentsdescribed herein, in such a case, X is CH and L is CH₂.

Another embodiment concerns compounds of other embodiments herein, e.g.,compounds of Formulas I, or II, or a pharmaceutically acceptable saltthereof, wherein X-L is CHCH₂; and Y is CH. From the embodimentsdescribed herein, in such a case, X is CH and L is CH₂.

Another embodiment concerns compounds of other embodiments herein, e.g.,compounds of Formulas I, or II, or a pharmaceutically acceptable saltthereof, wherein X-L is cyclopropyl; and Y is N.

In the embodiments where X-L is cyclopropyl, the compounds of FormulasI, or II would provide:

Another embodiment concerns compounds of Formulas I, II, III, IV, or V,wherein R⁴ is —CH₂CH₂OCH₃, C₁₋₃alkylene-R⁵, or C₁₋₃alkylene-R⁶, or apharmaceutically acceptable salt thereof.

Another embodiment concerns compounds of Formulas II, III, IV, or V,wherein R⁴ is as defined for compounds of Formula I, or apharmaceutically acceptable salt thereof.

Another embodiment concerns compounds of Formulas I, II, III, IV, or V,wherein R⁴ is —C₁₋₃alkyl, wherein said alkyl may be substituted asvalency allows with 0 to 1 substituent selected from—C₀₋₁alkylene-OR^(O), and —N(R^(N))₂, or a pharmaceutically acceptablesalt thereof.

Another embodiment concerns compounds of Formulas I, II, III, IV, or V,wherein R⁴ is —(CH₂)₂OCH₃, or —(CH₂)₂N(CH₃)₂, or a pharmaceuticallyacceptable salt thereof.

Another embodiment concerns compounds of Formulas I, II, III, IV, or V,wherein

R₄ is —CH₂—R⁵, wherein R⁵ is the 4- to 5-membered heterocycloalkyl,wherein said heterocycloalkyl may be substituted with 0 to 2substituents as valency allows independently selected from:

-   -   0 to 2 F atoms, and    -   0 to 1 substituent selected from —OCH₃ and —CH₂OCH₃;        or a pharmaceutically acceptable salt thereof.

Another embodiment concerns compounds of Formulas I, II, III, IV, or V,wherein the heterocycloalkyl is

wherein the heterocycloalkyl may be substituted with 0 to 2 substituentsas valency allows, e.g., replacing hydrogen, independently selectedfrom:

-   -   0 to 1 oxo (O═),    -   0 to 1 —CN,    -   0 to 2 F atoms, and    -   0 to 2 substituents independently selected from —C₁₋₃ alkyl and        —OC₁₋₃ alkyl, wherein the alkyl of C₁₋₃alkyl and OC₁₋₃ alkyl may        be independently substituted with 0 to 3 substituents as valency        allows independently selected from:        -   0 to 3 F atoms,        -   0 to 1-CN, and        -   0 to 1 —OR^(O),            or a pharmaceutically acceptable salt thereof.

Another embodiment concerns compounds of Formulas I, II, III, IV, or V,wherein the heterocycloalkyl is

wherein the heterocycloalkyl may be substituted with 0 to 2 substituentsas valency allows, e.g., replacing hydrogen, independently selectedfrom:

-   -   0 to 1 —CN,    -   0 to 2 F atoms, and    -   0 to 2 substituents independently selected from —C₁₋₃alkyl and        —OC₁₋₃alkyl, wherein the alkyl of C₁₋₃alkyl and OC₁₋₃alkyl may        be independently substituted with 0 to 3 substituents as valency        allows independently selected from:        -   0 to 3 F atoms,        -   0 to 1 —CN, and        -   0 to 1 —OR^(O), or a pharmaceutically acceptable salt            thereof.

Another embodiment concerns compounds of Formulas I, II, III, IV, or V,wherein the heterocycloalkyl is

wherein the heterocycloalkyl may be substituted with 0 to 1 substituentas valency allows, e.g., replacing hydrogen, selected from:

—CN,

F atom, and

-   -   0 to 1 substituent independently selected from —C₁₋₃alkyl and        —OC₁₋₃alkyl, wherein the alkyl of C₁₋₃alkyl and OC₁₋₃alkyl may        be substituted with 0 to 3 substituents as valency allows        independently selected from:        -   0 to 3 F atoms,        -   0 to 1-CN, and        -   0 to 1 —OR^(O),            or a pharmaceutically acceptable salt thereof.

Another embodiment concerns compounds of Formulas I, II, III, IV, or V,wherein the heterocycloalkyl is

or a pharmaceutically acceptable salt thereof.

Another embodiment concerns compounds of Formulas I, II, III, IV, or V,wherein the heterocycloalkyl is

wherein the heterocycloalkyl may be substituted as valency allows with 0to 1 methyl, wherein said methyl may be substituted with 0 to 3 F atoms,or a pharmaceutically acceptable salt thereof.

Another embodiment concerns compounds of Formulas I, II, III, IV, or V,wherein the heterocycloalkyl is

wherein the heterocycloalkyl is unsubstituted

Another embodiment concerns compounds of Formulas I, II, III, IV, or V,wherein —CH₂—R⁵ and the nitrogen to which R⁴ is attached provides:

or a pharmaceutically acceptable salt thereof.

Another embodiment concerns compounds of Formulas I, II, III, IV, or V,wherein

R₄ is —CH₂—R⁶, wherein R⁶ is the 5-membered heteroaryl, wherein saidheteroaryl may be substituted with 0 to 2 substituents as valency allowsindependently selected from:

-   -   0 to 2 halogens, wherein the halogen is independently selected        from F and C,    -   0 to 1 —OCH₃, and    -   0 to 1 —CH₃, —CH₂CH₃, —CF₃, or —CH₂CH₂OCH₃;        or a pharmaceutically acceptable salt thereof.

Another embodiment concerns compounds of Formulas I, II, III, IV, or V,wherein the heteroaryl is

wherein said heteroaryl may be substituted with 0 to 2 substituents asvalency allows, e.g., replacing hydrogen, independently selected from:

-   -   0 to 2 halogens, wherein the halogen is independently selected        from F and C,    -   0 to 1 substituent selected from —OR^(O) and —N(R^(N))₂, or    -   0 to 2 —C₁₋₃alkyl, wherein the alkyl may be substituted with 0        to 3 substituents as valency allows independently selected from:        -   0 to 3 F atoms, and        -   0 to 1 —OR^(O);            or a pharmaceutically acceptable salt thereof.

Another embodiment concerns compounds of Formulas I, II, III, IV, or V,wherein the heteroaryl is

wherein said heteroaryl may be substituted with 0 to 2 substituents asvalency allows, e.g., replacing hydrogen, independently selected from:

-   -   0 to 2 halogens, wherein the halogen is independently selected        from F and C,    -   0 to 1 substituent selected from —OR^(O) and —N(R^(N))₂, or    -   0 to 2 —C₁₋₃alkyl, wherein the alkyl may be substituted with 0        to 3 substituents as valency allows independently selected from:        -   0 to 3 F atoms, and        -   0 to 1 —OR^(O);

or a pharmaceutically acceptable salt thereof.

Another embodiment concerns compounds of Formulas I, II, III, IV, or V,wherein the heteroaryl is

wherein said heteroaryl may be substituted with 0 to 1 substituent asvalency allows with —C₁₋₂alkyl, wherein the alkyl may be substitutedwith 0 to 3 substituents as valency allows independently selected from:

-   -   0 to 3 F atoms, and    -   0 to 1 —OR^(O); and

each R^(O) is independently H, or —C₁₋₃alkyl;

or a pharmaceutically acceptable salt thereof. One will recognize thatany substituent would replace H on the carbon or nitrogen beingsubstituted. A non-limiting example of substituted heteroaryls are:

One will recognize that H is replaced with a substituent, e.g., R^(6s)(substituent allowed on any heteroaryl of R⁶), to provide:

wherein R^(6s) is —C₁₋₂alkyl, wherein the alkyl may be substituted with0 to 3 substituents as valency allows independently selected from:

-   -   0 to 3 F atoms, and    -   0 to 1 —OR^(O); and

each R^(O) is independently H, or —C₁₋₃alkyl;

or a pharmaceutically acceptable salt thereof.

Another embodiment concerns compounds of Formulas I, II, III, IV, or V,wherein the heteroaryl is

or a pharmaceutically acceptable salt thereof.

Another embodiment concerns compounds of other embodiments herein, e.g.,compounds of Formulas I, II, III, IV, or V, wherein Z¹, Z², and Z³ areeach CR^(Z), or a pharmaceutically acceptable salt thereof.

Another embodiment concerns compounds of other embodiments herein, e.g.,compounds of Formulas I, II, III, IV, or V, wherein R^(Z) is H, or apharmaceutically acceptable salt thereof.

Another embodiment concerns compounds of other embodiments herein, e.g.,compounds of Formulas I, II, III, IV, or V, wherein Z¹, Z², and Z³ areeach CH, or a pharmaceutically acceptable salt thereof.

Another embodiment concerns compounds of other embodiments herein, e.g.,compounds of Formulas I, II, III, IV, or V, wherein R³ is —CH₃, or —CF₃;and q is 1, or a pharmaceutically acceptable salt thereof.

Another embodiment concerns compounds of other embodiments herein, e.g.,compounds of Formulas I, II, III, IV, or V, wherein each R¹ isindependently F, C, or —CN, or a pharmaceutically acceptable saltthereof.

Another embodiment concerns compounds of other embodiments herein, e.g.,compounds of Formulas I, II, III, IV, or V, wherein R₄ is —CH₂—R⁵, or apharmaceutically acceptable salt thereof.

Another embodiment concerns compounds of other embodiments herein, e.g.,compounds of Formulas I, II, III, IV, or V, wherein R₄ is —CH₂—R⁶, or apharmaceutically acceptable salt thereof.

Another embodiment concerns compounds of other embodiments herein, e.g.,compounds of Formulas I, II, III, IV, or V, wherein the compound is thefree acid.

Another embodiment concerns any embodiment of compounds of Formulas I,II, III, IV, or V, wherein Ring A and R² provide:

or a pharmaceutically acceptable salt thereof, wherein

R is F, Cl, or —CN;

p is 0 or 1;

m is 0, 1, or 2; and

each R¹ is independently selected from halogen, —CN, —C₁₋₃alkyl, and—OC₁₋₃alkyl, wherein the alkyl of C₁₋₃alkyl and OC₁₋₃alkyl issubstituted with 0 to 3 F atoms.

Another embodiment concerns compounds of Formulas I, II, III, IV, or V,wherein R² is H, or a pharmaceutically acceptable salt thereof.

Another embodiment concerns compounds on the invention, wherein R² is H,or a pharmaceutically acceptable salt thereof.

Another embodiment concerns compounds on the invention, wherein thecompound is

-   2-({4-[2-(4-chloro-2-fluorophenyl)-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic    acid; or-   2-({4-[2-(4-chloro-2-fluorophenyl)-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-7-fluoro-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic    acid;    or a pharmaceutically acceptable salt thereof.-   Another embodiment concerns compounds on the invention, wherein the    compound is-   2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic    acid; or-   2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-7-fluoro-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic    acid;    or a pharmaceutically acceptable salt thereof.

Another embodiment concerns compounds on the invention, wherein R² isCH₃, or a pharmaceutically acceptable salt thereof.

Another embodiment concerns compounds on the invention, wherein thecompound is

-   2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic    acid;-   2-({4-[2-(4-Cyano-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic    acid;-   2-({4-[2-(5-Chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic    acid;-   2-({4-[2-(4-Chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-3-(1,3-oxazol-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic    acid;-   2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(1-ethyl-1H-imidazol-5-yl)methyl]-1H-benzimidazole-6-carboxylic    acid;-   2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-(1,3-oxazol-4-ylmethyl)-1H-benzimidazole-6-carboxylic    acid;-   2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-(pyridin-3-ylmethyl)-1H-benzimidazole-6-carboxylic    acid;-   2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-(1,3-oxazol-5-ylmethyl)-1H-benzimidazole-6-carboxylic    acid;-   2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(1-ethyl-1H-1,2,3-triazol-5-yl)methyl]-1H-benzimidazole-6-carboxylic    acid;-   2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-(1,3-oxazol-2-ylmethyl)-1H-benzimidazole-6-carboxylic    acid;-   2-({4-[2-(4-chloro-2-fluorophenyl)-7-fluoro-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic    acid;-   2-({4-[2-(4-cyano-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-(1,3-oxazol-2-ylmethyl)-1H-benzimidazole-6-carboxylic    acid; or-   2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-7-fluoro-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic    acid;    or a pharmaceutically acceptable salt thereof.

Another embodiment concerns compounds on the invention, wherein thecompound is

-   2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic    acid; or-   2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-7-fluoro-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic    acid;    or a pharmaceutically acceptable salt thereof.

Another embodiment concerns compounds on the invention, wherein thecompound is

-   2-({4-[(2S)-2-(4-Cyano-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic    acid;-   2-({4-[(2S)-2-(5-Chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic    acid; or-   2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(1-ethyl-1H-imidazol-5-yl)methyl]-1H-benzimidazole-6-carboxylic    acid;    or a pharmaceutically acceptable salt thereof.

Another embodiment concerns compounds on the invention, wherein thecompound is

-   2-({4-[(2R)-2-(4-Cyano-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic    acid;-   2-({4-[(2R)-2-(5-Chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic    acid; or-   2-({4-[(2R)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(1-ethyl-1H-imidazol-5-yl)methyl]-1H-benzimidazole-6-carboxylic    acid;    or a pharmaceutically acceptable salt thereof.

Another embodiment concerns compounds on the invention, wherein thecompound is

-   2-({4-[2-(4-Cyano-2-fluorophenyl)-2*-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic    acid, wherein chirality of 2* comes from C56;-   2-({4-[2-(5-Chloropyridin-2-yl)-2*-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic    acid, wherein chirality of 2* comes from P9;-   2-({4-[2-(4-chloro-2-fluorophenyl)-2*-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(1-ethyl-1H-imidazol-5-yl)methyl]-1H-benzimidazole-6-carboxylic    acid, wherein chirality of 2* comes from 17;-   2-({4-[2-(4-chloro-2-fluorophenyl)-7-fluoro-2*-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic    acid, wherein chirality of 2* comes from 96; or-   2-({4-[2-(4-cyano-2-fluorophenyl)-2*-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-(1,3-oxazol-2-ylmethyl)-1H-benzimidazole-6-carboxylic    acid, wherein chirality of 2* comes from C82;    or a pharmaceutically acceptable salt thereof.

Another embodiment includes a compound that is2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylicacid, or a pharmaceutically acceptable salt thereof, wherein the salt isa tris salt.

Another embodiment includes a compound that is2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylicacid, as a free acid.

Another embodiment includes a compound that is

or a pharmaceutically acceptable salt thereof.

Another embodiment includes a compound that is2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylicacid, or a pharmaceutically acceptable salt, wherein the salt is a trissalt {the tris salt of this compound is also known as:1,3-dihydroxy-2-(hydroxymethyl)propan-2-aminium2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylate}.

In some embodiments, the present invention provides a crystal form ofanhydrous tris salt of2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylicacid. In some further embodiments, the crystal form of anhydrous(anhydrate) tris salt of2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylicacid is designated as “Form I” that is characterized according to itsunique solid state signatures with respect to, for example, powder X-raydiffraction (PXRD), described herein (such as substantially as depictedin FIG. 1). In some embodiments, Form I exhibits a powder X-raydiffraction pattern comprising at least two characteristic peaks, interms of 2θ, selected from at 3.7±0.2°; 7.3±0.2°; 8.5±0.2°; 10.1±0.2°;14.7±0.2°; and 16.9±0.2°. In some embodiments, Form I exhibits a powderX-ray diffraction pattern comprising at least three characteristicpeaks, in terms of 2θ, selected from at 3.7±0.2°; 7.3±0.2°; 8.5±0.2°;10.1±0.2°; 14.7±0.2°; and 16.9±0.2°. In some embodiments, Form Iexhibits a powder X-ray diffraction pattern comprising at least fourcharacteristic peaks, in terms of 2θ, selected from at 3.7±0.2°;7.3±0.2°; 8.5±0.2°; 10.1±0.2°; 14.7±0.2°; and 16.9±0.2°. In someembodiments, Form I exhibits a powder X-ray diffraction patterncomprising at least five characteristic peaks, in terms of 2θ, selectedfrom at 3.7±0.2°; 7.3±0.2°; 8.5±0.2°; 10.1±0.2°; 14.7±0.2°; and16.9±0.2°.

In some embodiments, Form I exhibits a powder X-ray diffraction patterncomprising characteristic peaks, in terms of 2θ, at 3.7±0.2° and7.3±0.2°.

In some embodiments, Form I exhibits a powder X-ray diffraction patterncomprising peaks, in terms of 2θ, at 3.7±0.2°; 7.3±0.2°; and 14.7±0.2°.In some further embodiments, Form I exhibits the X-ray powderdiffraction pattern further comprises at least one peak, in terms of 2θ,selected from at 8.5±0.2°; 10.1±0.2°; and 16.9±0.2°.

In some embodiments, Form I exhibits a powder X-ray diffraction patterncomprising peaks, in terms of 2θ, at 3.7±0.2°; 7.3±0.2°; 14.7±0.2°; and16.9±0.2°.

In some embodiments, Form I exhibits a powder X-ray diffraction patterncomprising peaks, in terms of 2θ, at 3.7±0.2°; 7.3±0.2°; 8.5±0.2°;10.1±0.2°; 14.7±0.2°; and 16.9±0.2°.

In some embodiments, Form I exhibits a powder X-ray diffraction patternsubstantially as shown in FIG. 1. A list of diffraction peaks expressedin terms of the degree 2θ and relative intensities with a relativeintensity of 3.0% is provided above in Table X1.

As is well known in the art of powder diffraction, the relativeintensities of the peaks (reflections) can vary, depending upon thesample preparation technique, the sample mounting procedure and theparticular instrument employed. Moreover, instrument variation and otherfactors can affect the 2-theta values. Therefore, the XRPD peakassignments can vary by plus or minus about 0.2°.

Another embodiment includes a compound that is2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylicacid, as a free acid.

Another embodiment includes a compound that is

or a pharmaceutically acceptable salt thereof.

Another embodiment includes a compound that is

-   2-({4-[2-(5-Chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic    acid;-   2-({4-[(2S)-2-(5-Chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic    acid; or-   2-({4-[(2R)-2-(5-Chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic    acid; as the free acid.

Another embodiment includes a compound that is

-   2-({4-[2-(5-Chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic    acid;-   2-({4-[(2S)-2-(5-Chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic    acid; or-   2-({4-[(2R)-2-(5-Chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic    acid; or a pharmaceutically acceptable salt thereof, wherein the    salt is a tris salt.

Another embodiment includes a compound that is2-({4-[2-(5-Chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylicacid, DIAST-X2:

or pharmaceutically acceptable salt thereof. In some furtherembodiments, the present invention provides a compound that is2-({4-[2-(5-Chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylicacid, DIAST-X2, or tris salt [i.e.1,3-dihydroxy-2-(hydroxymethyl)propan-2-amine salt] thereof. The chiralcenter on the left part of the compound structure is marked as “abs” toindicate that chiral center has only one stereo-configuration (i.e., nota racemate with respect to that chiral center).

In some embodiments, the present invention provides a crystal form ofanhydrous tris salt of2-({4-[2-(5-Chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylicacid, DIAST-X2. In some further embodiments, the crystal form ofanhydrous (anhydrate) tris salt of2-({4-[2-(5-Chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylicacid, DIAST-X2, is designated as “Form A” that is characterizedaccording to its unique solid state signatures with respect to, forexample, powder X-ray diffraction (PXRD), described herein (such assubstantially as depicted in FIG. 2). In some embodiments, Form Aexhibits a powder X-ray diffraction pattern comprising at least twocharacteristic peaks, in terms of 2θ, selected from at 7.7±0.2°;15.2±0.2°; 15.7±0.2°; and 17.6±0.2°. In some embodiments, Form Aexhibits a powder X-ray diffraction pattern comprising at least threecharacteristic peaks, in terms of 2θ, selected from at 7.7±0.2°;15.2±0.2°; 15.7±0.2°; and 17.6±0.2°. In some embodiments, Form Aexhibits a powder X-ray diffraction pattern comprising characteristicpeaks, in terms of 2θ, selected from at 7.7±0.2°; 15.2±0.2°; 15.7±0.2°;and 17.6±0.2°.

In some embodiments, Form I exhibits a powder X-ray diffraction patterncomprising characteristic peaks, in terms of 2θ, at 7.7±0.2° and17.6±0.2°.

In some embodiments, Form A exhibits a powder X-ray diffraction patterncomprising peaks, in terms of 2θ, at 7.7±0.2°; 15.2±0.2°; and 17.6±0.2°.

In some embodiments, Form I exhibits a powder X-ray diffraction patterncomprising peaks, in terms of 2θ, at 7.7±0.2°; 15.2±0.2°; and 15.7±0.2°.

In some embodiments, Form I exhibits a powder X-ray diffraction patterncomprising peaks, in terms of 2θ, at 7.7±0.2°; 15.2±0.2°; 15.7±0.2°; and17.6±0.2°.

In some embodiments, Form A exhibits a powder X-ray diffraction patternsubstantially as shown in FIG. 2. A list of diffraction peaks expressedin terms of the degree 20 and relative intensities with a relativeintensity of 3.0% is provided above in Table X2.

As is well known in the art of powder diffraction, the relativeintensities of the peaks (reflections) can vary, depending upon thesample preparation technique, the sample mounting procedure and theparticular instrument employed. Moreover, instrument variation and otherfactors can affect the 2-theta values. Therefore, the XRPD peakassignments can vary by plus or minus about 0.2°.

In another embodiment, the invention provides a pharmaceuticalcomposition comprising a compound of Formulas I, II, III, IV, or V, or apharmaceutically acceptable salt thereof, as defined in any of theembodiments described herein, in admixture with at least onepharmaceutically acceptable excipient. This would include apharmaceutical composition comprising a compound of Formulas I, II, III,IV, or V, or a pharmaceutically acceptable salt thereof, as defined inany of the embodiments described herein, in admixture with at least onepharmaceutically acceptable excipient and one or more other therapeuticagent discussed herein.

The invention also includes the following embodiments:

a compound of Formulas I, II, III, IV, or V, or a pharmaceuticallyacceptable salt thereof, as defined in any of the embodiments describedherein, for use as a medicament;

a compound of Formulas I, II, III, IV, or V, or a pharmaceuticallyacceptable salt thereof, as defined in any of the embodiments describedherein, for use in the prevention and/or treatment of cardiometabolicand associated diseases discussed herein, including T2DM, pre-diabetes,NASH, and cardiovascular disease;

a method of treating a disease for which an agonist of GLP-1R isindicated, in a subject in need of such prevention and/or treatment,comprising administering to the subject a therapeutically effectiveamount of a compound of Formulas I, II, III, IV, or V, or apharmaceutically acceptable salt thereof, as defined in any of theembodiments described herein;

the use of a compound of Formulas I, II, III, IV, or V, or apharmaceutically acceptable salt thereof, as defined in any of theembodiments described herein, for the manufacture of a medicament fortreating a disease or condition for which an agonist of the GLP-1R isindicated;

a compound of Formulas I, II, III, IV, or V, or a pharmaceuticallyacceptable salt thereof, as defined in any of the embodiments describedherein, for use in the treatment of a disease or condition for which anagonist of GLP-1R is indicated; or

a pharmaceutical composition for the treatment of a disease or conditionfor which an agonist of the GLP-1R is indicated, comprising a compoundof Formulas I, II, III, IV, or V, or a pharmaceutically acceptable saltthereof, as defined in any of the embodiments described herein.

Every Example or pharmaceutically acceptable salt thereof may be claimedindividually or grouped together in any combination with any number ofeach and every embodiment described herein.

The invention also relates to a pharmaceutical composition comprising acompound of Formulas I, II, III, IV, or V, or a pharmaceuticallyacceptable salt thereof, as defined in any of the embodiments describedherein, for use in the treatment and/or prevention of cardiometabolicand associated diseases discussed herein, including T2DM, pre-diabetes,NASH, and cardiovascular disease.

Another embodiment of the invention concerns a compound of Formulas I,II, III, IV, or V, or a pharmaceutically acceptable salt thereof, asdefined in any of the embodiments described herein, for use in thetreatment and/or prevention of cardiometabolic and associated diseasesincluding diabetes (T1D and/or T2DM, including pre-diabetes), idiopathicT1D (Type 1b), latent autoimmune diabetes in adults (LADA), early-onsetT2DM (EOD), youth-onset atypical diabetes (YOAD), maturity onsetdiabetes of the young (MODY), malnutrition-related diabetes, gestationaldiabetes, hyperglycemia, insulin resistance, hepatic insulin resistance,impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy,kidney disease (e.g., acute kidney disorder, tubular dysfunction,proinflammatory changes to the proximal tubules), diabetic retinopathy,adipocyte dysfunction, visceral adipose deposition, sleep apnea, obesity(including hypothalamic obesity and monogenic obesity) and relatedcomorbidities (e.g., osteoarthritis and urine incontinence), eatingdisorders (including binge eating syndrome, bulimia nervosa, andsyndromic obesity such as Prader-Willi and Bardet-Biedl syndromes),weight gain from use of other agents (e.g., from use of steroids andantipsychotics), excessive sugar craving, dyslipidemia (includinghyperlipidemia, hypertriglyceridemia, increased total cholesterol, highLDL cholesterol, and low HDL cholesterol), hyperinsulinemia, NAFLD(including related diseases such as steatosis, NASH, fibrosis,cirrhosis, and hepatocellular carcinoma), cardiovascular disease,atherosclerosis (including coronary artery disease), peripheral vasculardisease, hypertension, endothelial dysfunction, impaired vascularcompliance, congestive heart failure, myocardial infarction (e.g.necrosis and apoptosis), stroke, hemorrhagic stroke, ischemic stroke,traumatic brain injury, pulmonary hypertension, restenosis afterangioplasty, intermittent claudication, post-prandial lipemia, metabolicacidosis, ketosis, arthritis, osteoporosis, Parkinson's Disease, leftventricular hypertrophy, peripheral arterial disease, maculardegeneration, cataract, glomerulosclerosis, chronic renal failure,metabolic syndrome, syndrome X, premenstrual syndrome, angina pectoris,thrombosis, atherosclerosis, transient ischemic attacks, vascularrestenosis, impaired glucose metabolism, conditions of impaired fastingplasma glucose, hyperuricemia, gout, erectile dysfunction, skin andconnective tissue disorders, psoriasis, foot ulcerations, ulcerativecolitis, hyper apo B lipoproteinemia, Alzheimer's Disease,schizophrenia, impaired cognition, inflammatory bowel disease, shortbowel syndrome, Crohn's disease, colitis, irritable bowel syndrome,prevention or treatment of Polycystic Ovary Syndrome and treatment ofaddiction (e.g., alcohol and/or drug abuse).

Abbreviations used herein are as follows:

The term “alkyl”, as used herein, means a straight or branched chainmonovalent hydrocarbon group of formula —C_(n)H_((2n+1)). Non-limitingexamples include methyl, ethyl, propyl, butyl, 2-methyl-propyl,1,1-dimethylethyl, pentyl and hexyl.

The term “alkylene”, as used herein, means a straight or branched chaindivalent hydrocarbon group of formula —C_(n)H_(2n)—. Non-limitingexamples include ethylene, and propylene.

The term “cycloalkyl”, as used herein, means a cyclic, monovalenthydrocarbon group of formula —C_(n)H_((2n−1)) containing at least threecarbon atoms. Non-limiting examples include cyclopropyl, cyclobutyl,cyclopentyl and cyclohexyl.

The term “halogen”, as used herein, refers to fluoride, chloride,bromide, or iodide.

The term “heterocycloalkyl”, as used herein, refers to a cycloalkylgroup in which one or more of the ring methylene groups (—CH₂—) has beenreplaced with a group selected from —O—, —S— or nitrogen, wherein thenitrogen may provide a point of attachment or may be substituted asprovided within each embodiment. Where nitrogen provides a point ofattachment, a structural drawing of a heterocycloalkyl would have anhydrogen on said nitrogen. Generally, the heterocycloalkyl may besubstituted with 0 to 2 substituents as valency allows independentlyselected from oxo, —CN, halogen, alkyl and —Oalkyl and the alkyl may befurther substituted. One will note that when there is 0 substitution,the heterocycloalkyl is unsubstituted.

The term “heteroaryl”, as used herein, refers to a monocyclic aromatichydrocarbon containing from 5 to 6 carbon atoms in which at least one ofthe ring carbon atoms has been replaced with a heteroatom selected fromoxygen, nitrogen and sulfur. Such a heteroaryl group may be attachedthrough a ring carbon atom or, where valency permits, through a ringnitrogen atom. Generally, the heteroaryl may be substituted with 0 to 2substituents as valency allows independently selected from halogen, OH,alkyl, O-alkyl, and amino (e.g., NH₂, NHalkyl, N(alkyl)₂), and the alkylmay be further substituted. One will note that when there is 0substitution, the heteroaryl is unsubstituted.

Room temperature: RT (15 to 25° C.).

Methanol: MeOH.

Ethanol: EtOH.

Isopropanol: iPrOH.

Ethyl acetate: EtOAc.

Tetrahydrofuran: THF.

Toluene: PhCH₃.

Cesium carbonate: Cs₂CO₃.

Lithium bis(trimethylsilyl)amide: LiHMDS.

Sodium t-butoxide: NaOtBu.

Potassium t-butoxide: KOtBu.

Lithium diisopropylamide: LDA.

Triethylamine: Et₃N.

N,N-diisopropylethyl amine: DIPEA.

Potassium carbonate: K₂CO₃.

Dimethyl formamide: DMF.

Dimethyl acetamide: DMAc.

Dimethyl sulfoxide: DMSO.

N-Methyl-2-pyrrolidinone: NMP.

Sodium hydride: NaH.

Trifluoroacetic acid: TFA.

Trifluoroacetic anhydride: TFAA.

Acetic anhydride: Ac₂O.

Dichloromethane: DCM.

1,2-Dichloroethane: DCE.

Hydrochloric acid: HCl.

1,8-Diazabicyclo[5.4.0]undec-7-ene: DBU.

Borane-dimethylsulfide complex: BH₃-DMS.

Borane-tetrahydrofuran complex: BH₃-THF.

Lithium aluminum hydride: LAH.

Acetic acid: AcOH.

Acetonitrile: MeCN.

p-Toluenesulfonic acid: pTSA.

Dibenzylidine acetone: DBA.

2,2′-Bis(diphenylphosphino)-1,1′-binaphthalene: BINAP.

1,1′-Ferrocenediyl-bis(diphenylphosphine): dppf.

1,3-Bis(diphenylphosphino)propane: DPPP.

3-Chloroperbenzoic acid: m-CPBA.

Tert-Butyl methyl ether: MTBE.

Methanesulfonyl: Ms.

N-Methylpyrrolidinone: NMP.

Thin layer chromatography: TLC.

Supercritical fluid chromatography: SFC.

4-(Dimethylamino)pyridine: DMAP.

Tert-Butyloxycarbonyl: Boc.

1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate: HATU.

Petroleum ether: PE.

2-(1H-Benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate: HBTU.

2-Amino-2-(hydroxymethyl)propane-1,3-diol: tris.

tris(dibenzylideneacetone)dipalladium: Pd₂(dba)₃

¹H Nuclear magnetic resonance (NMR) spectra were in all cases consistentwith the proposed structures. Characteristic chemical shifts (6) aregiven in parts-per-million relative to the residual proton signal in thedeuterated solvent (CHCl₃ at 7.27 ppm; CD₂HOD at 3.31 ppm; MeCN at 1.94ppm; DMSO at 2.50 ppm) and are reported using conventional abbreviationsfor designation of major peaks: e.g. s, singlet; d, doublet; t, triplet;q, quartet; m, multiplet; br, broad. The symbol {circumflex over( )}denotes that the ¹H NMR peak area was assumed because the peak waspartially obscured by water peak. The symbol {circumflex over( )}{circumflex over ( )} denotes that the ¹H NMR peak area was assumedbecause the peak was partially obscured by solvent peak.

As used herein, a wavy line,

denotes a point of attachment of a substituent to another group.

The compounds and intermediates described below were named using thenaming convention provided with ACD/ChemSketch 2012, File VersionC10H41, Build 69045 (Advanced Chemistry Development, Inc., Toronto,Ontario, Canada). The naming convention provided with ACD/ChemSketch2012 is well known by those skilled in the art and it is believed thatthe naming convention provided with ACD/ChemSketch 2012 generallycomports with the IUPAC (International Union for Pure and AppliedChemistry) recommendations on Nomenclature of Organic Chemistry and theCAS Index rules. One will note that the chemical names may have onlyparentheses or may have parentheses and brackets. The stereochemicaldescriptors may also be placed at different locations within the nameitself, depending on the naming convention. One of ordinary skill in theart will recognize these formatting variations and understand theyprovide the same chemical structure.

Pharmaceutically acceptable salts of the compounds of Formulas I, II,III, IV, or V include acid addition and base salts.

Suitable acid addition salts are formed from acids which form non-toxicsalts. Examples include the acetate, adipate, aspartate, benzoate,besylate, bicarbonate/carbonate, bisulfate/sulfate, borate, camsylate,citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate,gluconate, glucuronate, hexafluorophosphate, hibenzate,hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide,isethionate, lactate, malate, maleate, malonate, mesylate,methylsulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate,oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogenphosphate, pyroglutamate, saccharate, stearate, succinate, tannate,tartrate, tosylate, trifluoroacetate, 1,5-naphathalenedisulfonic acidand xinafoate salts.

Suitable base salts are formed from bases which form non-toxic salts.Examples include the aluminium, arginine, benzathine, calcium, choline,diethylamine, bis(2-hydroxyethyl)amine (diolamine), glycine, lysine,magnesium, meglumine, 2-aminoethanol (olamine), potassium, sodium,2-Amino-2-(hydroxymethyl)propane-1,3-diol (tris or tromethamine) andzinc salts.

Hemisalts of acids and bases may also be formed, for example,hemisulfate and hemicalcium salts. For a review on suitable salts, seeHandbook of Pharmaceutical Salts: Properties, Selection, and Use byStahl and Wermuth (Wiley-VCH, 2002).

Pharmaceutically acceptable salts of compounds of Formula I may beprepared by one or more of three methods:

-   (i) by reacting the compound of Formula I with the desired acid or    base;-   (ii) by removing an acid- or base-labile protecting group from a    suitable precursor of the compound of Formula I or by ring-opening a    suitable cyclic precursor, for example, a lactone or lactam, using    the desired acid or base; or-   (iii) by converting one salt of the compound of Formula I to another    by reaction with an appropriate acid or base or by means of a    suitable ion exchange column.

All three reactions are typically carried out in solution. The resultingsalt may precipitate out and be collected by filtration or may berecovered by evaporation of the solvent. The degree of ionisation in theresulting salt may vary from completely ionised to almost non-ionised.

The compounds of Formula I, and pharmaceutically acceptable saltsthereof, may exist in unsolvated and solvated forms. The term ‘solvate’is used herein to describe a molecular complex comprising the compoundof Formula I, or a pharmaceutically acceptable salt thereof, and one ormore pharmaceutically acceptable solvent molecules, for example,ethanol. The term ‘hydrate’ is employed when said solvent is water.

A currently accepted classification system for organic hydrates is onethat defines isolated site, channel, or metal-ion coordinatedhydrates—see Polymorphism in Pharmaceutical Solids by K. R. Morris (Ed.H. G. Brittain, Marcel Dekker, 1995). Isolated site hydrates are ones inwhich the water molecules are isolated from direct contact with eachother by intervening organic molecules. In channel hydrates, the watermolecules lie in lattice channels where they are next to other watermolecules. In metal-ion coordinated hydrates, the water molecules arebonded to the metal ion.

When the solvent or water is tightly bound, the complex may have awell-defined stoichiometry independent of humidity. When, however, thesolvent or water is weakly bound, as in channel solvates and hygroscopiccompounds, the water/solvent content may be dependent on humidity anddrying conditions. In such cases, non-stoichiometry will be the norm.

Also included within the scope of the invention are multi-componentcomplexes (other than salts and solvates) wherein the drug and at leastone other component are present in stoichiometric or non-stoichiometricamounts. Complexes of this type include clathrates (drug-host inclusioncomplexes) and co-crystals. The latter are typically defined ascrystalline complexes of neutral molecular constituents which are boundtogether through non-covalent interactions, but could also be a complexof a neutral molecule with a salt. Co-crystals may be prepared by meltcrystallisation, by recrystallisation from solvents, or by physicallygrinding the components together—see Chem Commun, 17, 1889-1896, by O.Almarsson and M. J. Zaworotko (2004). For a general review ofmulti-component complexes, see J Pharm Sci, 64 (8), 1269-1288, byHaleblian (August 1975).

The compounds of the invention may exist in a continuum of solid statesranging from fully amorphous to fully crystalline. The term ‘amorphous’refers to a state in which the material lacks long range order at themolecular level and, depending upon temperature, may exhibit thephysical properties of a solid or a liquid. Typically such materials donot give distinctive X-ray diffraction patterns and, while exhibitingthe properties of a solid, are more formally described as a liquid. Uponheating, a change from solid to liquid properties occurs which ischaracterised by a change of state, typically second order (‘glasstransition’). The term ‘crystalline’ refers to a solid phase in whichthe material has a regular ordered internal structure at the molecularlevel and gives a distinctive X-ray diffraction pattern with definedpeaks. Such materials when heated sufficiently will also exhibit theproperties of a liquid, but the change from solid to liquid ischaracterised by a phase change, typically first order (‘meltingpoint’).

The compounds of Formula I may also exist in a mesomorphic state(mesophase or liquid crystal) when subjected to suitable conditions. Themesomorphic state is intermediate between the true crystalline state andthe true liquid state (either melt or solution). Mesomorphism arising asthe result of a change in temperature is described as ‘thermotropic’ andthat resulting from the addition of a second component, such as water oranother solvent, is described as ‘lyotropic’. Compounds that have thepotential to form lyotropic mesophases are described as ‘amphiphilic’and consist of molecules which possess an ionic (such as —COO⁻Na⁺,—COO⁻K⁺, or —SO₃ ⁻Na⁺) or non-ionic (such as —N⁻N⁺(CH₃)₃) polar headgroup. For more information, see Crystals and the Polarizing Microscopeby N. H. Hartshorne and A. Stuart, 4^(th) Edition (Edward Arnold, 1970).

The compounds of Formula I may exhibit polymorphism and/or one or morekinds of isomerism (e.g. optical, geometric or tautomeric isomerism).The compounds of Formula I may also be isotopically labelled. Suchvariation is implicit to the compounds of Formula I defined as they areby reference to their structural features and therefore within the scopeof the invention.

Compounds of Formula I containing one or more asymmetric carbon atomscan exist as two or more stereoisomers. Where a compound of Formula Icontains an alkenyl or alkenylene group, geometric cis/trans (or Z/E)isomers are possible. Where structural isomers are interconvertible viaa low energy barrier, tautomeric isomerism (‘tautomerism’) can occur.This can take the form of proton tautomerism in compounds of Formula Icontaining, for example, an imino, keto, or oxime group, or so-calledvalence tautomerism in compounds which contain an aromatic moiety. Itfollows that a single compound may exhibit more than one type ofisomerism.

The pharmaceutically acceptable salts of compounds of Formula I may alsocontain a counterion which is optically active (e.g. d-lactate orI-lysine) or racemic (e.g. dl-tartrate or dl-arginine).

Cis/trans isomers may be separated by conventional techniques well knownto those skilled in the art, for example, chromatography and fractionalcrystallisation.

Conventional techniques for the preparation/isolation of individualenantiomers include chiral synthesis from a suitable optically pureprecursor or resolution of the racemate (or the racemate of a salt orderivative) using, for example, chiral high pressure liquidchromatography (HPLC). Alternatively, a racemic precursor containing achiral ester may be separated by enzymatic resolution (see, for example,Int J Mol Sci 29682-29716 by A. C. L. M. Carvaho et. al. (2015)). In thecase where the compound of Formula I contains an acidic or basic moiety,a salt may be formed with an optically pure base or acid such as1-phenylethylamine or tartaric acid. The resulting diastereomericmixture may be separated by fractional crystallization and one or bothof the diastereomeric salts converted to the corresponding pureenantiomer(s) by means well known to a skilled person. Alternatively,the racemate (or a racemic precursor) may be covalently reacted with asuitable optically active compound, for example, an alcohol, amine orbenzylic chloride. The resulting diastereomeric mixture may be separatedby chromatography and/or fractional crystallization by means well knownto a skilled person to give the separated diastereomers as singleenantiomers with 2 or more chiral centers. Chiral compounds of Formula I(and chiral precursors thereof) may be obtained inenantiomerically-enriched form using chromatography, typically HPLC, onan asymmetric resin with a mobile phase consisting of a hydrocarbon,typically heptane or hexane, containing from 0 to 50% by volume ofisopropanol, typically from 2% to 20%, and from 0 to 5% by volume of analkylamine, typically 0.1% diethylamine. Concentration of the eluateaffords the enriched mixture. Chiral chromatography using sub- andsupercritical fluids may be employed. Methods for chiral chromatographyuseful in some embodiments of the present invention are known in the art(see, for example, Smith, Roger M., Loughborough University,Loughborough, UK; Chromatographic Science Series (1998), 75 (SFC withPacked Columns), pp. 223-249 and references cited therein). In somerelevant examples herein, columns were obtained from ChiralTechnologies, Inc, West Chester, Pa., USA, a subsidiary of Daicel®Chemical Industries, Ltd., Tokyo, Japan.

When any racemate crystallises, crystals of two different types arepossible. The first type is the racemic compound (true racemate)referred to above wherein one homogeneous form of crystal is producedcontaining both enantiomers in equimolar amounts. The second type is theracemic mixture or conglomerate wherein two forms of crystal areproduced in equimolar amounts each comprising a single enantiomer. Whileboth of the crystal forms present in a racemic mixture have identicalphysical properties, they may have different physical propertiescompared to the true racemate. Racemic mixtures may be separated byconventional techniques known to those skilled in the art—see, forexample, Stereochemistry of Organic Compounds by E. L. Eliel and S. H.Wilen (Wiley, 1994).

It must be emphasised that the compounds of Formula I have been drawnherein in a single tautomeric form, all possible tautomeric forms areincluded within the scope of the invention.

The present invention includes all pharmaceutically acceptableisotopically-labeled compounds of Formula I wherein one or more atomsare replaced by atoms having the same atomic number, but an atomic massor mass number different from the atomic mass or mass number whichpredominates in nature.

Examples of isotopes suitable for inclusion in the compounds of theinvention include isotopes of hydrogen, such as ²H and ³H, carbon, suchas ¹¹C, ¹³C and ¹⁴C, chlorine, such as ³⁶Cl, fluorine, such as ¹⁸F,iodine, such as ¹²³I and ¹²⁵I, nitrogen, such as ¹³N and ¹⁵N, oxygen,such as ¹⁵O, ¹⁷O and ¹⁸O, phosphorus, such as ³²P, and sulfur, such as³⁵S.

Certain isotopically-labelled compounds of Formula I, for example thoseincorporating a radioactive isotope, are useful in drug and/or substratetissue distribution studies. The radioactive isotopes tritium, i.e. ³H,and carbon-14, i.e. ¹⁴C, are particularly useful for this purpose inview of their ease of incorporation and ready means of detection.

Substitution with heavier isotopes such as deuterium, i.e. ²H, mayafford certain therapeutic advantages resulting from greater metabolicstability, for example, increased in vivo half-life or reduced dosagerequirements.

Substitution with positron emitting isotopes, such as ¹¹C, ¹⁸F, ¹⁵O and¹³N, can be useful in Positron Emission Topography (PET) studies forexamining substrate receptor occupancy.

Isotopically-labeled compounds of Formula I can generally be prepared byconventional techniques known to those skilled in the art or byprocesses analogous to those described in the accompanying Examples andPreparations using an appropriate isotopically-labeled reagent in placeof the non-labeled reagent previously employed.

Pharmaceutically acceptable solvates in accordance with the inventioninclude those wherein the solvent of crystallization may be isotopicallysubstituted, e.g. D₂O, d₆-acetone, d₆-DMSO.

One way of carrying out the invention is to administer a compound ofFormula I in the form of a prodrug. Thus, certain derivatives of acompound of Formula I which may have little or no pharmacologicalactivity themselves can, when administered into or onto the body, beconverted into a compound of Formula I having the desired activity, forexample by hydrolytic cleavage, particularly hydrolytic cleavagepromoted by an esterase or peptidase enzyme. Such derivatives arereferred to as ‘prodrugs’. Further information on the use of prodrugsmay be found in ‘Pro-drugs as Novel Delivery Systems’, Vol. 14, ACSSymposium Series (T. Higuchi and W. Stella) and ‘Bioreversible Carriersin Drug Design’, Pergamon Press, 1987 (Ed. E. B. Roche, AmericanPharmaceutical Association). Reference can also be made to NatureReviews/Drug Discovery, 2008, 7, 355 and Current Opinion in DrugDiscovery and Development, 2007, 10, 550.

Prodrugs in accordance with the invention can, for example, be producedby replacing appropriate functionalities present in the compounds ofFormula I with certain moieties known to those skilled in the art as‘pro-moieties’ as described, for example, in ‘Design of Prodrugs’ by H.Bundgaard (Elsevier, 1985) and Y. M. Choi-Sledeski and C. G. Wermuth,‘Designing Prodrugs and Bioprecursors’ in Practice of MedicinalChemistry, (Fourth Edition), Chapter 28, 657-696 (Elsevier, 2015).

Thus, a prodrug in accordance with the invention is (a) an ester oramide derivative of a carboxylic acid in a compound of Formula I; (b) anester, carbonate, carbamate, phosphate or ether derivative of a hydroxylgroup in a compound of Formula I; (c) an amide, imine, carbamate oramine derivative of an amino group in a compound form Formula I; (d) anoxime or imine derivative of a carbonyl group in a compound of FormulaI; or (e) a methyl, primary alcohol or aldehyde group that can bemetabolically oxidized to a carboxylic acid in a compound of Formula I.

Some specific examples of prodrugs in accordance with the inventioninclude:

-   (i) where the compound of Formula I contains a carboxylic acid    functionality (—COOH), an ester thereof, such as a compound wherein    the hydrogen of the carboxylic acid functionality of the compound of    Formula I is replaced by C₁-C₈ alkyl (e.g. ethyl) or (C₁-C₈    alkyl)C(═O)OCH₂— (e.g. ^(t)BuC(═O)OCH₂—);-   (ii) where the compound of Formula I contains an alcohol    functionality (—OH), an ester thereof, such as a compound wherein    the hydrogen of the alcohol functionality of the compound of Formula    I is replaced by —CO(C₁-C₈ alkyl) (e.g. methylcarbonyl) or the    alcohol is esterified with an amino acid;-   (iii) where the compound of Formula I contains an alcohol    functionality (—OH), an ether thereof, such as a compound wherein    the hydrogen of the alcohol functionality of the compound of Formula    I is replaced by (C₁-C₈ alkyl)C(═O)OCH₂— or —CH₂OP(═O)(OH)₂;-   (iv) where the compound of Formula I contains an alcohol    functionality (—OH), a phosphate thereof, such as a compound wherein    the hydrogen of the alcohol functionality of the compound of Formula    I is replaced by —P(═O)(OH)₂ or —P(═O)(ONa)₂ or —P(═O)(O⁻)₂Ca²⁺;-   (v) where the compound of Formula I contains a primary or secondary    amino functionality (—NH₂ or —NHR where R≠H), an amide thereof, for    example, a compound wherein, as the case may be, one or both    hydrogens of the amino functionality of the compound of Formula I    is/are replaced by (C₁-C₁₀)alkanoyl, —COCH₂NH₂ or the amino group is    derivatised with an amino acid;-   (vi) where the compound of Formula I contains a primary or secondary    amino functionality (—NH₂ or —NHR where R H), an amine thereof, for    example, a compound wherein, as the case may be, one or both    hydrogens of the amino functionality of the compound of Formula I    is/are replaced by —CH₂OP(═O)(OH)₂;-   (vii) where the carboxylic acid group within compound of Formula I    is replaced by a methyl group, a —CH₂OH group or an aldehyde group.

Certain compounds of Formula I may themselves act as prodrugs of othercompounds of Formula I. It is also possible for two compounds of FormulaI to be joined together in the form of a prodrug. In certaincircumstances, a prodrug of a compound of Formula I may be created byinternally linking two functional groups in a compound of Formula I, forinstance by forming a lactone.

References to compounds of Formula I are taken to include the compoundsthemselves and prodrugs thereof. The invention includes such compoundsof Formula I as well as pharmaceutically acceptable salts of suchcompounds and pharmaceutically acceptable solvates of said compounds andsalts.

Administration and Dosing

Typically, a compound of the invention is administered in an amounteffective to treat a condition as described herein. The compounds of theinvention can be administered as compound per se, or alternatively, as apharmaceutically acceptable salt. For administration and dosingpurposes, the compound per se or pharmaceutically acceptable saltthereof will simply be referred to as the compounds of the invention.

The compounds of the invention are administered by any suitable route inthe form of a pharmaceutical composition adapted to such a route, and ina dose effective for the treatment intended. The compounds of theinvention may be administered orally, rectally, vaginally, parenterally,or topically.

The compounds of the invention may be administered orally. Oraladministration may involve swallowing, so that the compound enters thegastrointestinal tract, or buccal or sublingual administration may beemployed by which the compound enters the bloodstream directly from themouth.

In another embodiment, the compounds of the invention may also beadministered directly into the bloodstream, into muscle, or into aninternal organ. Suitable means for parenteral administration includeintravenous, intraarterial, intraperitoneal, intrathecal,intraventricular, intraurethral, intrasternal, intracranial,intramuscular and subcutaneous.

Suitable devices for parenteral administration include needle (includingmicroneedle) injectors, needle-free injectors and infusion techniques.

In another embodiment, the compounds of the invention may also beadministered topically to the skin or mucosa, that is, dermally ortransdermally. In another embodiment, the compounds of the invention canalso be administered intranasally or by inhalation. In anotherembodiment, the compounds of the invention may be administered rectallyor vaginally. In another embodiment, the compounds of the invention mayalso be administered directly to the eye or ear.

The dosage regimen for the compounds of the invention and/orcompositions containing said compounds is based on a variety of factors,including the type, age, weight, sex and medical condition of thepatient; the severity of the condition; the route of administration; andthe activity of the particular compound employed. Thus the dosageregimen may vary widely. In one embodiment, the total daily dose of acompound of the invention is typically from about 0.001 to about 100mg/kg (i.e., mg compound of the invention per kg body weight) for thetreatment of the indicated conditions discussed herein. In anotherembodiment, total daily dose of the compound of the invention is fromabout 0.01 to about 30 mg/kg, and in another embodiment, from about 0.03to about 10 mg/kg, and in yet another embodiment, from about 0.1 toabout 3. It is not uncommon that the administration of the compounds ofthe invention will be repeated a plurality of times in a day (typicallyno greater than 4 times). Multiple doses per day typically may be usedto increase the total daily dose, if desired.

For oral administration, the compositions may be provided in the form oftablets containing 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 30.0 50.0,75.0, 100, 125, 150, 175, 200, 250 and 500 milligrams of the activeingredient for the symptomatic adjustment of the dosage to the patient.A medicament typically contains from about 0.01 mg to about 500 mg ofthe active ingredient, or in another embodiment, from about 1 mg toabout 100 mg of active ingredient. Intravenously, doses may range fromabout 0.01 to about 10 mg/kg/minute during a constant rate infusion.

Suitable subjects according to the invention include mammalian subjects.In one embodiment, humans are suitable subjects. Human subjects may beof either gender and at any stage of development.

Pharmaceutical Compositions

In another embodiment, the invention comprises pharmaceuticalcompositions. Such pharmaceutical compositions comprise a compound ofthe invention presented with a pharmaceutically acceptable carrier.Other pharmacologically active substances can also be present. As usedherein, “pharmaceutically acceptable carrier” includes any and allsolvents, dispersion media, coatings, antibacterial and antifungalagents, isotonic and absorption delaying agents, and the like that arephysiologically compatible. Examples of pharmaceutically acceptablecarriers include one or more of water, saline, phosphate bufferedsaline, dextrose, glycerol, ethanol and the like, as well ascombinations thereof, and may include isotonic agents, for example,sugars, sodium chloride, or polyalcohols such as mannitol, or sorbitolin the composition. Pharmaceutically acceptable substances such aswetting agents or minor amounts of auxiliary substances such as wettingor emulsifying agents, preservatives or buffers, which enhance the shelflife or effectiveness of the antibody or antibody portion.

The compositions of this invention may be in a variety of forms. Theseinclude, for example, liquid, semi-solid and solid dosage forms, such asliquid solutions (e.g., injectable and infusible solutions), dispersionsor suspensions, tablets, pills, powders, liposomes and suppositories.The form depends on the intended mode of administration and therapeuticapplication.

Typical compositions are in the form of injectable or infusiblesolutions, such as compositions similar to those used for passiveimmunization of humans with antibodies in general. One mode ofadministration is parenteral (e.g. intravenous, subcutaneous,intraperitoneal, intramuscular). In another embodiment, the antibody isadministered by intravenous infusion or injection. In yet anotherembodiment, the antibody is administered by intramuscular orsubcutaneous injection.

Oral administration of a solid dose form may be, for example, presentedin discrete units, such as hard or soft capsules, pills, cachets,lozenges, or tablets, each containing a predetermined amount of at leastone compound of the invention. In another embodiment, the oraladministration may be in a powder or granule form. In anotherembodiment, the oral dose form is sub-lingual, such as, for example, alozenge. In such solid dosage forms, the compounds of Formula I areordinarily combined with one or more adjuvants. Such capsules or tabletsmay contain a controlled release formulation. In the case of capsules,tablets, and pills, the dosage forms also may comprise buffering agentsor may be prepared with enteric coatings.

In another embodiment, oral administration may be in a liquid dose form.Liquid dosage forms for oral administration include, for example,pharmaceutically acceptable emulsions, solutions, suspensions, syrups,and elixirs containing inert diluents commonly used in the art (e.g.,water). Such compositions also may comprise adjuvants, such as wetting,emulsifying, suspending, flavoring (e.g., sweetening), and/or perfumingagents.

In another embodiment, the invention comprises a parenteral dose form.“Parenteral administration” includes, for example, subcutaneousinjections, intravenous injections, intraperitoneally, intramuscularinjections, intrasternal injections, and infusion. Injectablepreparations (i.e., sterile injectable aqueous or oleaginoussuspensions) may be formulated according to the known art using suitabledispersing, wetting agents, and/or suspending agents.

In another embodiment, the invention comprises a topical dose form.“Topical administration” includes, for example, transdermaladministration, such as via transdermal patches or iontophoresisdevices, intraocular administration, or intranasal or inhalationadministration. Compositions for topical administration also include,for example, topical gels, sprays, ointments, and creams. A topicalformulation may include a compound which enhances absorption orpenetration of the active ingredient through the skin or other affectedareas. When the compounds of this invention are administered by atransdermal device, administration will be accomplished using a patcheither of the reservoir and porous membrane type or of a solid matrixvariety. Typical formulations for this purpose include gels, hydrogels,lotions, solutions, creams, ointments, dusting powders, dressings,foams, films, skin patches, wafers, implants, sponges, fibres, bandagesand microemulsions. Liposomes may also be used. Typical carriers includealcohol, water, mineral oil, liquid petrolatum, white petrolatum,glycerin, polyethylene glycol and propylene glycol. Penetrationenhancers may be incorporated—see, for example, B. C. Finnin and T. M.Morgan, J. Pharm. Sci., vol. 88, pp. 955-958, 1999.

Formulations suitable for topical administration to the eye include, forexample, eye drops wherein the compound of this invention is dissolvedor suspended in a suitable carrier. A typical formulation suitable forocular or aural administration may be in the form of drops of amicronized suspension or solution in isotonic, pH-adjusted, sterilesaline. Other formulations suitable for ocular and aural administrationinclude ointments, biodegradable (i.e., absorbable gel sponges,collagen) and non-biodegradable (i.e., silicone) implants, wafers,lenses and particulate or vesicular systems, such as niosomes orliposomes. A polymer such as crossed linked polyacrylic acid, polyvinylalcohol, hyaluronic acid, a cellulosic polymer, for example,hydroxypropylmethylcellulose, hydroxyethylcellulose, or methylcellulose,or a heteropolysaccharide polymer, for example, gelan gum, may beincorporated together with a preservative, such as benzalkoniumchloride. Such formulations may also be delivered by iontophoresis.

For intranasal administration or administration by inhalation, thecompounds of the invention are conveniently delivered in the form of asolution or suspension from a pump spray container that is squeezed orpumped by the patient or as an aerosol spray presentation from apressurized container or a nebulizer, with the use of a suitablepropellant. Formulations suitable for intranasal administration aretypically administered in the form of a dry powder (either alone, as amixture, for example, in a dry blend with lactose, or as a mixedcomponent particle, for example, mixed with phospholipids, such asphosphatidylcholine) from a dry powder inhaler or as an aerosol sprayfrom a pressurized container, pump, spray, atomizer (preferably anatomizer using electrohydrodynamics to produce a fine mist), ornebulizer, with or without the use of a suitable propellant, such as1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane. Forintranasal use, the powder may comprise a bioadhesive agent, forexample, chitosan or cyclodextrin.

In another embodiment, the invention comprises a rectal dose form. Suchrectal dose form may be in the form of, for example, a suppository.Cocoa butter is a traditional suppository base, but various alternativesmay be used as appropriate.

Other carrier materials and modes of administration known in thepharmaceutical art may also be used. Pharmaceutical compositions of theinvention may be prepared by any of the well-known techniques ofpharmacy, such as effective formulation and administration procedures.The above considerations in regard to effective formulations andadministration procedures are well known in the art and are described instandard textbooks. Formulation of drugs is discussed in, for example,Hoover, John E., Remington's Pharmaceutical Sciences, Mack PublishingCo., Easton, Pa., 1975; Liberman et al., Eds., Pharmaceutical DosageForms, Marcel Decker, New York, N.Y., 1980; and Kibbe et al., Eds.,Handbook of Pharmaceutical Excipients (3rd Ed.), American PharmaceuticalAssociation, Washington, 1999.

Co-Administration

The compounds of the invention can be used alone, or in combination withother therapeutic agents. The invention provides any of the uses,methods or compositions as defined herein wherein the compound of anyembodiment of Formula I herein, or pharmaceutically acceptable saltthereof, or pharmaceutically acceptable solvate of said compound orsalt, is used in combination with one or more other therapeutic agentdiscussed herein. This would include a pharmaceutical composition forthe treatment of a disease or condition for which an agonist of theGLP-1R is indicated, comprising a compound of Formulas I, II, III, IV,or V, or a pharmaceutically acceptable salt thereof, as defined in anyof the embodiments described herein, and one or more other therapeuticagent discussed herein.

The administration of two or more compounds “in combination” means thatall of the compounds are administered closely enough in time that eachmay generate a biological effect in the same time frame. The presence ofone agent may alter the biological effects of the other compound(s). Thetwo or more compounds may be administered simultaneously, concurrentlyor sequentially. Additionally, simultaneous administration may becarried out by mixing the compounds prior to administration or byadministering the compounds at the same point in time but as separatedosage forms at the same or different site of administration.

The phrases “concurrent administration,” “co-administration,”“simultaneous administration,” and “administered simultaneously” meanthat the compounds are administered in combination.

In another embodiment, the invention provides methods of treatment thatinclude administering compounds of the present invention in combinationwith one or more other pharmaceutical agents, wherein the one or moreother pharmaceutical agents may be selected from the agents discussedherein.

In one embodiment, the compounds of this invention are administered withan anti-diabetic agent including but not limited to a biguanide (e.g.,metformin), a sulfonylurea (e.g., tolbutamide, glibenclamide,gliclazide, chlorpropamide, tolazamide, acetohexamide, glyclopyramide,glimepiride, or glipizide), a thiazolidinedione (e.g., pioglitazone,rosiglitazone, or lobeglitazone), a glitazar (e.g., saroglitazar,aleglitazar, muraglitazar or tesaglitazar), a meglitinide (e.g.,nateglinide, repaglinide), a dipeptidyl peptidase 4 (DPP-4) inhibitor(e.g., sitagliptin, vildagliptin, saxagliptin, linagliptin, gemigliptin,anagliptin, teneligliptin, alogliptin, trelagliptin, dutogliptin, oromarigliptin), a glitazone (e.g., pioglitazone, rosiglitazone,balaglitazone, rivoglitazone, or lobeglitazone), a sodium-glucose linkedtransporter 2 (SGLT2) inhibitor (e.g., empagliflozin, canagliflozin,dapagliflozin, ipragliflozin, Ipragliflozin, tofogliflozin, sergliflozinetabonate, remogliflozin etabonate, or ertugliflozin), an SGLTL1inhibitor, a GPR40 agonist (FFAR1/FFA1 agonist, e.g. fasiglifam),glucose-dependent insulinotropic peptide (GIP) and analogues thereof, analpha glucosidase inhibitor (e.g. voglibose, acarbose, or miglitol), oran insulin or an insulin analogue, including the pharmaceuticallyacceptable salts of the specifically named agents and thepharmaceutically acceptable solvates of said agents and salts.

In another embodiment, the compounds of this invention are administeredwith an anti-obesity agent including but not limited to peptide YY or ananalogue thereof, a neuropeptide Y receptor type 2 (NPYR2) agonist, aNPYR1 or NPYR5 antagonist, a cannabinoid receptor type 1 (CB1R)antagonist, a lipase inhibitor (e.g., orlistat), a human proisletpeptide (HIP), a melanocortin receptor 4 agonist (e.g., setmelanotide),a melanin concentrating hormone receptor 1 antagonist, a farnesoid Xreceptor (FXR) agonist (e.g. obeticholic acid), zonisamide, phentermine(alone or in combination with topiramate), a norepinephrine/dopaminereuptake inhibitor (e.g., buproprion), an opioid receptor antagonist(e.g., naltrexone), a combination of norepinephrine/dopamine reuptakeinhibitor and opioid receptor antagonist (e.g., a combination ofbupropion and naltrexone), a GDF-15 analog, sibutramine, acholecystokinin agonist, amylin and analogues therof (e.g.,pramlintide), leptin and analogues thereof (e.g., metroleptin), aserotonergic agent (e.g., lorcaserin), a methionine aminopeptidase 2(MetAP2) inhibitor (e.g., beloranib or ZGN-1061), phendimetrazine,diethylpropion, benzphetamine, an SGLT2 inhibitor (e.g., empagliflozin,canagliflozin, dapagliflozin, ipragliflozin, Ipragliflozin,tofogliflozin, sergliflozin etabonate, remogliflozin etabonate, orertugliflozin), an SGLTL1 inhibitor, a dual SGLT2/SGLT1 inhibitor, afibroblast growth factor receptor (FGFR) modulator, an AMP-activatedprotein kinase (AMPK) activator, biotin, a MAS receptor modulator, or aglucagon receptor agonist (alone or in combination with another GLP-1Ragonist, e.g., liraglutide, exenatide, dulaglutide, albiglutide,lixisenatide, or semaglutide), including the pharmaceutically acceptablesalts of the specifically named agents and the pharmaceuticallyacceptable solvates of said agents and salts.

In another embodiment, the compounds of this invention are administeredin combination with one or more of the following: an agent to treat NASHincluding but not limited to PF-05221304, an FXR agonist (e.g.,obeticholic acid), a PPAR α/δ agonist (e.g., elafibranor), a syntheticfatty acid-bile acid conjugate (e.g., aramchol), a caspase inhibitor(e.g., emricasan), an anti-lysyl oxidase homologue 2 (LOXL2) monoclonalantibody (e.g., simtuzumab), a galectin 3 inhibitor (e.g., GR-MD-02), aMAPK5 inhibitor (e.g., GS-4997), a dual antagonist of chemokine receptor2 (CCR2) and CCR5 (e.g., cenicriviroc), a fibroblast growth factor 21(FGF21) agonist (e.g., BMS-986036), a leukotriene D4 (LTD4) receptorantagonist (e.g., tipelukast), a niacin analogue (e.g., ARI 3037MO), anASBT inhibitor (e.g., volixibat), an acetyl-CoA carboxylase (ACC)inhibitor (e.g., NDI 010976 or PF-05221304), a ketohexokinase (KHK)inhibitor, a diacylglyceryl acyltransferase 2 (DGAT2) inhibitor, a CB1receptor antagonist, an anti-CB1R antibody, or an apoptosissignal-regulating kinase 1 (ASK1) inhibitor, including thepharmaceutically acceptable salts of the specifically named agents andthe pharmaceutically acceptable solvates of said agents and salts.

Some specific compounds that can be used in combination with thecompounds of the present invention for treating diseases or disordersdescribed herein (e.g. NASH) include:

4-(4-(1-Isopropyl-7-oxo-1,4,6,7-tetrahydrospiro[indazole-5,4′-piperidine]-1′-carbonyl)-6-methoxypyridin-2-yl)benzoicacid, which is an example of a selective ACC inhibitor and was preparedas the free acid in Example 9 of U.S. Pat. No. 8,859,577, which is theU.S. national phase of International Application No. PCT/IB2011/054119,the disclosures of which are hereby incorporated herein by reference intheir entireties for all purposes. Crystal forms of4-(4-(1-Isopropyl-7-oxo-1,4,6,7-tetrahydrospiro[indazole-5,4′-piperidine]-1′-carbonyl)-6-methoxypyridin-2-yl)benzoicacid, including an anhydrous mono-tris form (Form 1) and a trihydrate ofthe mono-tris salt (Form 2), are described in International PCTApplication No. PCT/B2018/058966, the disclosure of which is herebyincorporated herein by reference in its entirety for all purposes;

(S)-2-(5-((3-Ethoxypyridin-2-yl)oxy)pyridin-3-yl)-N-(tetrahydrofuran-3-yl)pyrimidine-5-carboxamide,or a pharmaceutically acceptable salt thereof, and its crystalline solidforms (Form 1 and Form 2) is an example of a DGAT2 inhibitor describedin Example 1 of U.S. Pat. No. 10,071,992, the disclosure of which ishereby incorporated herein by reference in its entirety for allpurposes;

[(1R,5S,6R)-3-{2-[(2S)-2-methylazetidin-1-yl]-6-(trifluoromethyl)pyrimidin-4-yl}-3-azabicyclo[3.1.0]hex-6-yl]aceticacid, or a pharmaceutically acceptable salt thereof, (including acrystalline free acid form thereof) is an example of a ketohexokinaseinhibitor and is described in Example 4 of U.S. Pat. No. 9,809,579, thedisclosure of which is hereby incorporated herein by reference in itsentirety for all purposes; and

the FXR agonist Tropifexor or a pharmaceutically acceptable salt thereofis described in Example 1-1B of U.S. Pat. No. 9,150,568, the disclosureof which is hereby incorporated herein by reference in its entirety forall purposes.

These agents and compounds of the invention can be combined withpharmaceutically acceptable vehicles such as saline, Ringer's solution,dextrose solution, and the like. The particular dosage regimen, i.e.,dose, timing and repetition, will depend on the particular individualand that individual's medical history.

Acceptable carriers, excipients, or stabilizers are nontoxic torecipients at the dosages and concentrations employed, and may comprisebuffers such as phosphate, citrate, and other organic acids; salts suchas sodium chloride; antioxidants including ascorbic acid and methionine;preservatives (such as octadecyldimethylbenzyl ammonium chloride;hexamethonium chloride; benzalkonium chloride, benzethonium chloride;phenol, butyl or benzyl alcohol; alkyl parabens, such as methyl orpropyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; andm-cresol); low molecular weight (less than about 10 residues)polypeptides; proteins, such as serum albumin, gelatin, or Igs;hydrophilic polymers such as polyvinylpyrrolidone; amino acids such asglycine, glutamine, asparagine, histidine, arginine, or lysine;monosaccharides, disaccharides, and other carbohydrates includingglucose, mannose, or dextrins; chelating agents such as EDTA; sugarssuch as sucrose, mannitol, trehalose or sorbitol; salt-formingcounter-ions such as sodium; metal complexes (e.g., Zn-proteincomplexes); and/or non-ionic surfactants such as TWEEN™, PLURONICS™ orpolyethylene glycol (PEG).

Liposomes containing these agents and/or compounds of the invention areprepared by methods known in the art, such as described in U.S. Pat.Nos. 4,485,045 and 4,544,545. Liposomes with enhanced circulation timeare disclosed in U.S. Pat. No. 5,013,556. Particularly useful liposomescan be generated by the reverse phase evaporation method with a lipidcomposition comprising phosphatidylcholine, cholesterol andPEG-derivatized phosphatidylethanolamine (PEG-PE). Liposomes areextruded through filters of defined pore size to yield liposomes withthe desired diameter.

These agents and/or the compounds of the invention may also be entrappedin microcapsules prepared, for example, by coacervation techniques or byinterfacial polymerization, for example, hydroxymethylcellulose orgelatin-microcapsules and poly-(methylmethacrylate) microcapsules,respectively, in colloidal drug delivery systems (for example,liposomes, albumin microspheres, microemulsions, nano-particles andnanocapsules) or in macroemulsions. Such techniques are disclosed inRemington, The Science and Practice of Pharmacy, 20th Ed., MackPublishing (2000).

Sustained-release preparations may be used. Suitable examples ofsustained-release preparations include semi-permeable matrices of solidhydrophobic polymers containing the compound of Formulas I, II, III, IV,or V, which matrices are in the form of shaped articles, e.g., films, ormicrocapsules. Examples of sustained-release matrices includepolyesters, hydrogels (for example, poly(2-hydroxyethyl-methacrylate),or ‘poly(vinylalcohol)), polylactides (U.S. Pat. No. 3,773,919),copolymers of L-glutamic acid and 7 ethyl-L-glutamate, non-degradableethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymerssuch as those used in LUPRON DEPOT™ (injectable microspheres composed oflactic acid-glycolic acid copolymer and leuprolide acetate), sucroseacetate isobutyrate, and poly-D-(−)-3-hydroxybutyric acid.

The formulations to be used for intravenous administration must besterile. This is readily accomplished by, for example, filtrationthrough sterile filtration membranes. Compounds of the invention aregenerally placed into a container having a sterile access port, forexample, an intravenous solution bag or vial having a stopper pierceableby a hypodermic injection needle.

Suitable emulsions may be prepared using commercially available fatemulsions, such as Intralipid™, Liposyn™, Infonutrol™, Lipofundin™ andLipiphysan™. The active ingredient may be either dissolved in apre-mixed emulsion composition or alternatively it may be dissolved inan oil (e.g., soybean oil, safflower oil, cottonseed oil, sesame oil,corn oil or almond oil) and an emulsion formed upon mixing with aphospholipid (e.g., egg phospholipids, soybean phospholipids or soybeanlecithin) and water. It will be appreciated that other ingredients maybe added, for example glycerol or glucose, to adjust the tonicity of theemulsion. Suitable emulsions will typically contain up to 20% oil, forexample, between 5 and 20%. The fat emulsion can comprise fat dropletsbetween 0.1 and 1.0 μm, particularly 0.1 and 0.5 μm, and have a pH inthe range of 5.5 to 8.0.

The emulsion compositions can be those prepared by mixing a compound ofthe invention with Intralipid™ or the components thereof (soybean oil,egg phospholipids, glycerol and water).

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as set outabove. In some embodiments, the compositions are administered by theoral or nasal respiratory route for local or systemic effect.Compositions in preferably sterile pharmaceutically acceptable solventsmay be nebulised by use of gases. Nebulised solutions may be breatheddirectly from the nebulising device or the nebulising device may beattached to a face mask, tent or intermittent positive pressurebreathing machine. Solution, suspension or powder compositions may beadministered, preferably orally or nasally, from devices which deliverthe formulation in an appropriate manner.

Kits

Another aspect of the invention provides kits comprising the compound ofFormulas I, II, III, IV, or V or pharmaceutical compositions comprisingthe compound of Formulas I, II, III, IV, or V of the invention. A kitmay include, in addition to the compound of Formulas I, II, or III, ofthe invention or pharmaceutical composition thereof, diagnostic ortherapeutic agents. A kit may also include instructions for use in adiagnostic or therapeutic method. In some embodiments, the kit includesthe compound of Formulas I, II, III, IV, or V, or a pharmaceuticalcomposition thereof and a diagnostic agent. In other embodiments, thekit includes the compound of Formulas I, II, III, IV, or V, or apharmaceutical composition thereof.

In yet another embodiment, the invention comprises kits that aresuitable for use in performing the methods of treatment describedherein. In one embodiment, the kit contains a first dosage formcomprising one or more of the compounds of the invention in quantitiessufficient to carry out the methods of the invention. In anotherembodiment, the kit comprises one or more compounds of the invention inquantities sufficient to carry out the methods of the invention and acontainer for the dosage and a container for the dosage.

Preparation

The compounds of Formulas I, II, III, IV, or V, may be prepared by thegeneral and specific methods described below, using the common generalknowledge of one skilled in the art of synthetic organic chemistry. Suchcommon general knowledge can be found in standard reference books suchas Comprehensive Organic Chemistry, Ed. Barton and Ollis, Elsevier;Comprehensive Organic Transformations: A Guide to Functional GroupPreparations, Larock, John Wiley and Sons; and Compendium of OrganicSynthetic Methods, Vol. I-XII (published by Wiley-Interscience). Thestarting materials used herein are commercially available or may beprepared by routine methods known in the art.

In the preparation of the compounds of Formulas I, II, III, IV, or V, itis noted that some of the preparation methods described herein mayrequire protection of remote functionality (e.g., primary amine,secondary amine, carboxyl in Formula I precursors). The need for suchprotection will vary depending on the nature of the remote functionalityand the conditions of the preparation methods. The need for suchprotection is readily determined by one skilled in the art. The use ofsuch protection/deprotection methods is also within the skill in theart. For a general description of protecting groups and their use, seeT. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons,New York, 1991.

For example, certain compounds contain primary amines or carboxylic acidfunctionalities which may interfere with reactions at other sites of themolecule if left unprotected. Accordingly, such functionalities may beprotected by an appropriate protecting group which may be removed in asubsequent step. Suitable protecting groups for amine and carboxylicacid protection include those protecting groups commonly used in peptidesynthesis (such as N-t-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz),and 9-fluorenylmethylenoxycarbonyl (Fmoc) for amines and lower alkyl orbenzyl esters for carboxylic acids) which are generally not chemicallyreactive under the reaction conditions described and can typically beremoved without chemically altering other functionality in the Formula Icompounds.

The Schemes described below are intended to provide a generaldescription of the methodology employed in the preparation of thecompounds of the present invention. Some of the compounds of the presentinvention may contain single or multiple chiral centers with thestereochemical designation (R) or (S). It will be apparent to oneskilled in the art that all of the synthetic transformations can beconducted in a similar manner whether the materials are enantioenrichedor racemic. Moreover the resolution to the desired optically activematerial may take place at any desired point in the sequence using wellknown methods such as described herein and in the chemistry literature.For example, intermediates (e.g., S4, S7, S8, S24, S40, and S41) andfinals (e.g., S25 and S42) may be separated using chiral chromatographicmethods. Alternatively, chiral salts may be utilized to isolateenantiomerically enriched intermediates and final compounds.

In the Schemes that follow, the variables X, Y, Z¹, Z², Z³, R, R¹, R²,R³, R⁴, m, p, and q are as described herein for compounds of Formulas I,II, III, IV, or V unless otherwise noted. For simplicity, the variable Ais used to denote Ring A and its optional substituent R¹. For theSchemes provided below, each X¹, X², X³, and X⁴ can independently be aleaving group such as any alkyl or aryl sulfonate (e.g., mesylate,tosylate, or triflate), or a halogen or any other group that can bedisplaced by an amine or utilized in a metal mediated coupling reaction.X⁴ may also be a protected carboxylic acid (i.e., ester). When theprotecting group is identified as Pg¹, it can be an alkyl amineprotecting group such as benzyl, benzhydryl, allyl, or the like; acarbamate protecting group such as Boc, Cbz, or the like; or an amideprotecting group such trifluoroacetamide. When the protecting group isidentified as Pg², it can be an acid protecting group such as methyl,ethyl, benzyl, t-butyl or the like. When the protecting group isidentified as Pg³, it can be an alcohol protecting group such astrimethylsilylethoxyethyl; or an acyl group like acetyl, benzoyl or thelike; or a trialkylsilyl group such as trimethylsilyl,tert-butyldimethylsilyl, triisopropylsilyl or the like. R^(2a) is H or—C₁₋₂alkyl, wherein alkyl may have 0 to 1 OH. R^(4a) is C₁₋₂ alkyl,C₀₋₂alkylene-C₃₋₆cycloalkyl, C₀₋₂alkylene-R⁵, or C₁₋₂alkylene-R⁶,wherein said alkyl, alkylene, or cycloalkyl may be independentlysubstituted as valency allows with 0 to 3 F atoms and 0 to 1 substituentindependently selected from C₀₋₁alkylene-OR^(O) and —N(R^(N))₂.

The substituted piperidine S8, where R²═H and Y═CH, may be prepared asdiscussed in Scheme 1. Aryl or heteroaryl bromide S1 can be treated withan alkyl lithium, for example butyl lithium or tert-butyl lithium, togive an aryl- or heteroaryl-lithium species that may react with aldehydeS2 to give diol S3. Other aryl or heteroaryl organometallic reagents,such as, but not limited to, Grignard reagents, may also be used in thepreparation of S3. The reaction is typically conducted at a termperaturearound −70° C. Diol S3 may then be oxidized with NalO₄ to provide acetalS4 (R²═H). Compound S4 may then be reacted with a substituted boronicacid or boronate ester (S5) in the presence of a palladium catalyst andligand complex in the manner of a Suzuki reaction (Maluenda and Navarro,Molecules, 2015, 20, 7528-7557) to provide compounds of the generalformula S6. Reduction of the olefin to provide compounds of generalstructure S7 could be performed under an atmosphere of hydrogen (15-100psi H₂) in an alcoholic solvent such as MeOH or EtOH or alternatively anaprotic organic solvent such as EtOAc or THF in the presence of anappropriate catalyst such as palladium on carbon, Pd(OH)₂ on carbon(Pearlman's catalyst), PtO₂ (Adams catalyst), ortris(triphenylphosphine)rhodium(I) chloride (Wilkinson's catalyst).Transfer hydrogenation reagents, for example ammonium formate ordihydrobenzene, or similar, may be employed using suitable catalyst.Alternatively, the reduction may be accomplished by alternative methodsknow to those skilled in the art using reagents such as triethyl silaneor other silanes, under acid or metallic catalysis, or metallicreductants, such as magnesium or similar. Alternatively, the olefin canbe functionalized by methods known to one skilled in the art tointroduce R³ groups. For example, the olefin could be hydroborated toproduce an alcohol that could be alkylated or further converted to anitrile, F or alkyl group. Removal of Pg¹ could be effected with manymethods described in literature to provide amines S8.

Scheme 2 provides an alternative preparation of compounds of generalstructure S4. Reaction of appropriately substituted diols of generalstructure S9 with aldehydes or ketones of general structure S10a in thepresence of a an acid such as p-toluenesulfonic acid or pyridiniump-toluenesulfonate in aprotic organic solvent such as toluene or benzenemay deliver compounds of the general structure S4. The reaction istypically heated at reflux using a Dean-Stark trap to azeotropicallyremove water. Diols S9 may also be reacted with cyclic (dotted lineexists) or acyclic (dotted line is absent) acetals or ketals of generalstructure S10b under acidic catalysis. The same is applicable withcyclic or acyclic thioacetals or thioketals of general structure S10cunder the influence of mercury salts, mild oxidants or alkylatingreagents, to provide compounds S4. Alternatively, diols of generalformula S9 may be reacted with appropriately substituted alkyne S11 inan aprotic solvent such as toluene in the presence trirutheniumdodecacarbonyl at a temperature around 100° C. to deliver compounds ofthe general structure S4 where R²═CH₂R^(2a). In cases where R² containsan alcohol functional group, such as CH₂OH, an alcohol protecting group(Pg³), such as acetate, may be incorporated into compounds of generalstructure S10. The protecting group may then be removed in a subsequentstep. Intermediate S4 may then be further modified using methodsdescribed for Scheme 1 to provide amines of general structure S8.

As provided in Scheme 3, conversion of S4 to compounds of generalstructure S7 where Y═N can be accomplished by such manner as aBuchwald-Hartwig C—N coupling between compounds of the general structureS4 and an appropriately substituted and protected piperazine S12 in thepresence of a palladium or copper catalyst and ligand complex. Thesereactions are generally performed between 0 and 110° C. in aproticorganic solvents such as but not limited to 1,4-dioxane and PhCH₃ withadded base such as Cs₂CO₃, LiHMDS or NaOtBu. Removal of Pg¹ could beeffected with many methods described in literature to provide amines S8where Y═N.

Amine compounds S8 prepared via methods described in Schemes 1-3 can bealkylated with a protected 2-bromoacetate in the presence of a suitablebase such as K₂CO₃, Et₃N, NaH or LiHMDS in a polar aprotic solvent suchas but not limited to DMF, DMAc, DMSO or NMP to deliver compounds of thegeneral structure S13 (X═N, L=CH₂). Standard ester hydrolysis can beperformed to provide acids S14. If Pg² is t-butyl, standard acidicdeprotection methods such as TFA/DCM, HCl/1,4-dioxane, HCl/EtOAc orother suitable conditions may be used to deliver acids S14. If Pg² ismethyl or ethyl, standard basic deprotection methods such as aqueousNaOH in methanol or ethanol, or other suitable conditions may be used todeliver acids S14.

Compounds of general structure S15 (Scheme 5) can react with aminesR⁴NH₂ in the presence of bases such as sodium-, potassium-, or cesiumcarbonate, -bicarbonate, hydroxide, acetate, or an organic amine basesuch as Et₃N, DIPEA, DBU, and the like in a polar aprotic solvent suchas but not limited to THF, DMF, DMAc, DMSO or NMP or a protic solventsuch as water, MeOH, EtOH or iPrOH or a mixture thereof to delivercompounds of the general structure S16. One will note that if an exampleprovides an R⁴ with a resolved enantiomeric center, the other enantiomeror a racemix mixture thereof could be obtained by selection of theappropriate starting material. Preferred X³ substituents include F, Cl,and Br, preferred X⁴ groups include Cl, Br, and —CO₂-Pg². Reduction ofthe nitro group can be affected by hydrogenation at 1-6 atm H₂ with ametal catalyst such as palladium on carbon or Raney nickel in a proticsolvent such as MeOH or EtOH or aprotic solvent such as DMF, THF orEtOAc. Alternatively, the nitro group may be reduced with iron, zinc,SnCl₂ or other suitable metal in an acidic media such as 1N HCl, AcOH oraqueous NH₄Cl in THF or methanol to provide compounds of generalstructure S17 (Scheme 5a). Compounds such as S18 may be acylated by acylhalides by standard fashion or by carboxylates via standard amidecoupling protocols to provide compounds S19. Reduction to compounds S20may be performed under standard conditions with reducing agents such asLAH or BH₃-THF or BH₃-DMS (Scheme 5b).

Diamine compounds S17 and S20 prepared via methods described in Schemes5a and 5b, collectively designated as diamine S21 (Scheme 6), may beacylated with acids of general structure S14 under standard amidecoupling protocols to deliver amides S22 which will exist as a mixturefrom 100% S22a to 100% S22b. This mixture of amines S22 may be cyclizedto deliver compounds of general structure S23 by a variety of methods.Amines S22 may be heated with a dehydrating agent such as T₃P® or analkyl alcohol such as n-butanol under microwave conditions (10-60 min at120-180° C.) to deliver compounds S23. Alternatively, the mixture ofcompounds S22 may be heated under acidic conditions such as AcOH from60-100° C. or under basic conditions such as aqueous NaOH or KOH in1,4-dioxane from 60-100° C. to provide S23. Compounds of generalstructure S23 (X⁴═Cl, Br or I) can be converted to esters of structureS24 by palladium-catalyzed carbonylation under a 15-100 psi carbonmonoxide atmosphere at a temperature from 20-100 at a temperature from20-100° C. with an appropriate alcohol such as MeOH or EtOH or otheralkyl alcohol. Hydrolysis of ester S24 can be performed as described inScheme 4 to provide acids S25. For compounds S22 where X⁴═CO₂-Pg²conversion to ester S24 proceeds under similar conditions as describedpreviously except for use of the basic cyclization method where compoundS25 may be isolated directly from the reaction mixture. For compoundsS24 where X⁴ is CO₂tBu, deprotection to acid S25 can be performed underacidic conditions described in Scheme 4. Alternatively, for compoundsS24 where Pg² is a CC alkyl, such as methyl, ethyl, hexyl or octyl, theester deprotection may be performed with a variety of enzymes includingesterases, proteases, peptidases, lipases, and glycosidases which arewell known to those skilled in the art. The hydrolysis may also beperformed by treating the ester with an aqueous solution of1,5,7-triazabicyclo[4.4.0]dec-5-ene at RT.

Additionally, diamine S21 may be converted to the 2-chloromethylbenzimidazole S26 (Scheme 7) by several methods. Treatment with2-chloroacetyl chloride or chloroacetic anhydride in an aprotic solventsuch as 1,4-dioxane followed by heating at 40-100° C. for 2-18 h candeliver the desired benzimidazole S26 where Z¹, Z² and Z³ are CH. In thecases where Z¹, Z² and Z³ are not all CR^(Z), after treatment with2-chloroacetyl chloride in an aprotic solvent such as 1,4-dioxane for 30min to 4 h, the solvent is exchanged for an acidic media such as AcOH orTFA followed by heating at 40-100° C. for 2-18 h to provide the desiredcompound S26. Diamine S21 can also be treated with chloroaceticanhydride at a temperature between 0 and 80° C. in an aprotic solventsuch as, but not limited to 1,4-dioxane, THF or MeCN, followed byheating for 2 to 18 h at 60-100° C. to deliver the desired compound S26.In addition, diamine S21 can be treated with2-chloro-1,1,1-trimethoxyethane in an aprotic solvent such as, but notlimited to 1,4-dioxane, THF or MeCN, or a protic solvent, e.g., MeOH orEtOH, in the presence of an acid catalyst, e.g., pTSA, at 20-100° C.Alternatively, diamines S21 may be heated 100-180° C. with2-hydroxyacetic acid in an aprotic solvent, such as but not limited tomesitylene, to provide a hydroxymethyl intermediate. Conversion of thehydroxymethyl group to the chloromethyl compound S26 may be accomplishedby standard methods, including treatment with SOCl₂ in an aproticsolvent. Compounds of general structure S26 can be reacted withcompounds S8 in the presence of bases such as sodium-, potassium-, orcesium carbonate, -bicarbonate, NaH or an organic amine base such asEt₃N, DIPEA, DBU, and the like in a polar aprotic solvent, such as butnot limited to THF, MeCN, DMF, DMAc, DMSO or NMP, to deliver compoundsS23 (X⁴═Cl, Br, I) or compounds S24 (X⁴═CO₂-Pg²) that are then used toobtain compounds S25 via methods described in Scheme 6.

Alternatively (Scheme 8), compounds of general structure S26 can bereacted with appropriately substituted and protected piperazines S12, inthe presence of bases such as sodium-, potassium-, or cesium carbonate,-bicarbonate, NaH or an organic amine base such as Et₃N, DIPEA, DBU, andthe like in a polar aprotic solvent, such as but not limited to THF,MeCN, DMF, DMAc, DMSO or NMP, to provide compounds S27 (Scheme 8).Removal of Pg¹ could be effected with many methods described inliterature to provide amines S28. Conversion to compounds of generalstructure S23 (X⁴═Cl, Br or I) or S24 (X⁴═CO₂-Pg²) can be accomplishedby such manner as a Buchwald-Hartwig C—N coupling between compounds ofthe general structures S4 and as described previously in Scheme 3.Compounds of general structure S23 or S24 can then be used to obtaincompounds of structure S25 via methods described in Scheme 6.

Compounds of general structure S25 may also be prepared as discussed inScheme 9. Diol S9 can be protected to give S29. Thetrimethylsilylethoxymethyl group is a preferred protecting group.Protection of the diol as the corresponding acetal, for example theformaldehyde acetal, is also preferred. Compound S29 may then be reactedwith a substituted boronic acid or boronate ester (S5) and the olefinthen reduced with methods described in Scheme 1 to provide compounds ofthe general formula S31 where Y═CH. Alternatively, compound S29 may becoupled with piperazines of general structure S12 using methodsdescribed in Scheme 3 to provide S31 where Y═N. Compounds of generalstructure S31 may be deprotected and then coupled with S26 to givecompounds of general structure S33 using methods described in Scheme 7.Alternatively, compounds of general structure S33 may be prepared fromS32 by conversion of S32 to the corresponding N-acetic acid derivativeand subsequent condensations with diamines S21 as described in Schemes 4and 6. Deprotection of S33 using methods know to those skilled in theart may provide diols of general structure S34 which may then react withalkynes of general structure S11 using methods described in Scheme 2 toprovide S23 or S24. Alternatively, S34 may be converted to S23 or S24using aldehydes, ketones or their derivatives, as discussed in Scheme 2.Compounds of general structure S23 or S24 can then be used to obtaincompounds of structure S25 via methods described in Scheme 6.

Compounds of general structures S24 and S33 where Y═N andX-L=cyclopropyl may be prepared as discussed in Scheme 10. Protectedpiperidinone S35 may be homologated to unsaturated ester S36 usingmethods well known to those skilled in the art. For example,Horner-Wadsworth-Emmons olefination of S42 with a phosphonate, such asethyl (diethoxyphosphoryl)acetate, that has been deprotonated with astrong base such as lithium, sodium or potassium tert-butoxide, mayprovide S36. The reaction is typically conducted in an aprotic solventlike THF or DME, at a temperature around 0 to −50° C. Conversion of S36to the cyclopropane derivative S37 may be accomplished by treatment withsulfoxonium ylid derived from trimethylsulfoxonium iodide and a base,such as potassium tert-butoxide or sodium hydride. Deprotection of S37and subsequent coupling of the resulting carboxylic acid S38 with S21,where X⁴=CO₂Pg², using methods described in Scheme 6 may providecompounds of general formula S39. Deprotection of S39 and coupling withS4 using methods described in Scheme 3 may give compounds of generalstructure S24 where Y═N and X-L is cyclopropyl. Compounds of generalstructure S24 can then be used to obtain compounds of structure S25 viamethods described in Scheme 6. Alternatively, S40 may be reacted withS29 using methods described in Scheme 3 to provide S33 where Y═N andX-L=cyclopropyl. Compounds of general structure S33 can then be used toobtain compounds of structure S25 via methods described in Scheme 6 and9.

Alternatively, compounds of the general structure S25 where Y═N and X-Lis cyclopropyl may be prepared as described in Scheme 11. Removal of Pg¹from S37 provides piperidine derivative S43. Coupling of S43 with S4 ina manner similar to that described in Scheme 3 provides S13 where Y═Nand X-L is cyclopropyl. Deprotection may then provide compounds ofgeneral structure S14 that may then be used to prepare S25 as describedin Scheme 6.

EXAMPLES

The following illustrate the synthesis of non-limiting compounds of thepresent invention Additional compounds within the scope of thisinvention may be prepared using the methods illustrated in theseExamples, either alone or in combination with techniques generally knownin the art.

Experiments were generally carried out under inert atmosphere (nitrogenor argon), particularly in cases where oxygen- or moisture-sensitivereagents or intermediates were employed. Commercial solvents andreagents were generally used without further purification. Anhydroussolvents were employed where appropriate, generally AcroSeal® productsfrom Acros Organics, Aldrich® Sure/Seal™ from Sigma-Aldrich, or DriSolv®products from EMD Chemicals. In other cases, commercial solvents werepassed through columns packed with 4 Å molecular sieves, until thefollowing QC standards for water were attained: a) <100 ppm fordichloromethane, toluene, N,N-dimethylformamide, and tetrahydrofuran; b)<180 ppm for methanol, ethanol, 1,4-dioxane, and diisopropylamine. Forvery sensitive reactions, solvents were further treated with metallicsodium, calcium hydride, or molecular sieves, and distilled just priorto use. Products were generally dried under vacuum before being carriedon to further reactions or submitted for biological testing. Massspectrometry data is reported from either liquid chromatography-massspectrometry (LCMS), atmospheric pressure chemical ionization (APCI) orgas chromatography-mass spectrometry (GCMS) instrumentation. The symbol♦ denotes that the chlorine isotope pattern was observed in the massspectrum. Chiral separations were used to separate enantiomers ordiastereomers of some intermediates during the preparation of thecompounds of the invention. When chiral separation was done, theseparated enantiomers were designated as ENT-1 or ENT-2 (or DIAST-1 orDIAST-2), according to their order of elution. In some embodiments,enantiomers designated as ENT-1 or ENT-2 can be used as startingmaterials to prepare other enantiomers or diastereomers. In suchsituations, the resulting enantiomers prepared are designated as ENT-X1and ENT-X2, respectively, according to their starting materials;similarly, the diastereomers prepared are designated as DIAST-X1 andDIAST-X2, respectively, (or DIAST-according to their starting materials.DIAST-Y and DIAST-Z nomenclature is used similarly, in synthesesemploying multiple intermediates.

For compounds with two chiral centers, the stereoisomers at eachstereocenter were separated at different times. The designation of ENT-1or ENT-2 (or DIAST-1 or DIAST-2) of an intermediate or an example refersto the order of elution for the separation done at that step. It isrecognized that when stereoisomers at a chiral center are separated in acompound with two or more centers, the separated enantiomers arediastereomers of each other. By way of example, but not limitation,Examples 15 and 16 have two chiral centers. The chiral center of thecyclopropyl moiety was separated when intermediate C36 was separatedinto ENT-1, giving intermediate P17, and ENT-2, giving intermediate P18.P18 was then used in preparing C70, which had one stereoisomer enrichedat the cyclopropyl chiral carbon and a mixture of stereoisomers at thedioxolane carbon. C70 was then separated into DIAST-Y1 at the dioxolanecarbon, giving intermediate C71, and DIAST-Y2 at the dioxolane carbon,giving intermediate C72, where these intermediates are enriched in asingle stereoisomer. C71 was then used to prepare Example 15, which isidentified by name as2-{6-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]-6-azaspiro[2.5]oct-1-yl}-1-(2-methoxyethyl)-1H-benzimidazole-6-carboxylicacid, DIAST-X1, trifluoroacetate salt [from P18 via C71]. In thesepreparations, after a mixture is subjected to separation procedures, thechiral center is identified with “abs” near that center, with theunderstanding that the separated enantiomers may not be enantiomericallypure. Typically, the enriched enantiomer at each chiral center is >90%of the isolated material. Preferably, the enriched enantiomer at eachcenter is >98% of the mixture.

In some examples, the optical rotation of an enantiomer was measuredusing a polarimeter. According to its observed rotation data (or itsspecific rotation data), an enantiomer with a clockwise rotation wasdesignated as the (+)-enantiomer and an enantiomer with acounter-clockwise rotation was designated as the (−)-enantiomer. Racemiccompounds are indicated either by the absence of drawn or describedstereochemistry, or by the presence of (+/−) adjacent to the structure;in this latter case, indicated stereochemistry represents the relative(rather than absolute) configuration of the compound's substituents.

Reactions proceeding through detectable intermediates were generallyfollowed by LCMS, and allowed to proceed to full conversion prior toaddition of subsequent reagents. For syntheses referencing procedures inother Examples or Methods, reaction conditions (reaction time andtemperature) may vary. In general, reactions were followed by thin-layerchromatography or mass spectrometry, and subjected to work-up whenappropriate. Purifications may vary between experiments: in general,solvents and the solvent ratios used for eluents/gradients were chosento provide appropriate R_(f)s or retention times. All starting materialsin these Preparations and Examples are either commercially available orcan be prepared by methods known in the art or as described herein.

Preparation P1 tert-Butyl4-[2-(4-chloro-2-fluorophenyl)-1,3-benzodioxol-4-yl]piperidine-1-carboxylate(P1)

Step 1. Synthesis of2-bromo-6-[(4-chloro-2-fluorophenyl)(hydroxy)methyl]phenol (C1)

This experiment was carried out in two batches of the same scale.n-Butyllithium (2.5 M solution in hexanes; 32.8 mL, 82.0 mmol) wasslowly added to a −70° C. solution of 1-bromo-4-chloro-2-fluorobenzene(17.2 g, 82.1 mmol) in diethyl ether (100 mL), while the temperature ofthe reaction mixture was maintained below −60° C. After the reactionmixture had been stirred at −70° C. for 20 minutes, a solution of3-bromo-2-hydroxybenzaldehyde (5.5 g, 27 mmol) in diethyl ether (100 mL)was slowly added, while the reaction temperature was maintained below−60° C. After a further 1 hour of stirring at −70° C., the reaction wasquenched by addition of aqueous ammonium chloride solution (50 mL) at−70° C., and the resulting mixture was diluted with water (100 mL). Thetwo batches were combined at this point and extracted with ethyl acetate(400 mL); the organic layer was washed with saturated aqueous sodiumchloride solution (200 mL), dried over sodium sulfate, filtered, andconcentrated in vacuo. Silica gel chromatography (Gradient: 0% to 7%ethyl acetate in petroleum ether) afforded C1 as a white solid. Combinedyield: 15.7 g, 47.4 mmol, 88%. ¹H NMR (400 MHz, chloroform-d) δ 7.44(dd, J=8.0, 1.5 Hz, 1H), 7.37 (dd, J=8.1, 8.1 Hz, 1H), 7.15 (br dd,J=8.5, 2.1 Hz, 1H), 7.12-7.05 (m, 2H), 6.80 (dd, J=7.8, 7.8 Hz, 1H),6.78 (s, 1H), 6.31 (d, J=4.8 Hz, 1H), 3.02 (br d, J=4.9 Hz, 1H).

Step 2. Synthesis of4-bromo-2-(4-chloro-2-fluorophenyl)-1,3-benzodioxole (C2)

To a solution of C1 (15.7 g, 47.4 mmol) in methanol (450 mL) was added asolution of sodium periodate (25.4 g, 119 mmol) in water (105 mL), andthe reaction mixture was stirred at 30° C. for 16 hours, whereupon itwas concentrated in vacuo. After the residue had been diluted withdichloromethane (500 mL), it was washed with water (500 mL). Thedichloromethane solution was then dried over sodium sulfate, filtered,and concentrated in vacuo. Purification via silica gel chromatography(Eluent: petroleum ether) provided C2 as a white solid. Yield: 10.0 g,30.3 mmol, 64%. The following ¹H NMR data was obtained from anexperiment carried out in the same manner but on smaller scale. ¹H NMR(400 MHz, DMSO-d₆) δ 7.67-7.61 (m, 2H), 7.50 (s, 1H), 7.43 (br dd, J=8,2 Hz, 1H), 7.09 (dd, J=8.3, 1.1 Hz, 1H), 7.01 (dd, J=7.9, 1.1 Hz, 1H),6.86 (dd, J=8.1, 8.1 Hz, 1H).

Step 3. Synthesis of tert-butyl4-[2-(4-chloro-2-fluorophenyl)-1,3-benzodioxol-4-yl]-3,6-dihydropyridine-1(2H)-carboxylate(C3)

A reaction flask containing a suspension of C2 (8.00 g, 24.3 mmol),tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate(9.01 g, 29.1 mmol), sodium carbonate (5.15 g, 48.6 mmol), and[1,1′-bis(diphenylphosphino)ferrocene]dichloro-palladium(II)[Pd(dppf)Cl₂; 888 mg, 1.21 mmol] in 1,4-dioxane (80 mL) and water (32mL) was evacuated and charged with nitrogen. This evacuation cycle wasrepeated twice, and then the reaction mixture was stirred at 90° C. for16 hours. After removal of solvent in vacuo, the residue was partitionedbetween ethyl acetate (200 mL) and water (200 mL). The organic layer waswashed with saturated aqueous sodium chloride solution (100 mL), driedover sodium sulfate, filtered, and concentrated under reduced pressure.Chromatography on silica gel (Gradient: 0% to 4.3% ethyl acetate inpetroleum ether) provided the product, which was combined with materialfrom a similar reaction carried out using C2 (2.00 g, 6.07 mmol) toafford C3 as a light-yellow gum. Combined yield: 10.3 g, 23.8 mmol, 78%.¹H NMR (400 MHz, chloroform-d) δ 7.53 (dd, J=8.3, 7.8 Hz, 1H), 7.23-7.16(m, 3H), 6.88-6.83 (m, 2H), 6.81-6.76 (m, 1H), 6.34-6.28 (br m, 1H),4.10-4.05 (m, 2H), 3.61 (br dd, J=6, 5 Hz, 2H), 2.59-2.50 (br m, 2H),1.48 (s, 9H).

Step 4. Synthesis of tert-butyl4-[2-(4-chloro-2-fluorophenyl)-1,3-benzodioxol-4-yl]piperidine-1-carboxylate(P1)

A solution of C3 (10.3 g, 23.8 mmol) andtris(triphenylphosphine)rhodium(I) chloride (Wilkinson's catalyst; 1.54g, 1.66 mmol) in methanol (100 mL) was stirred at 50° C. under hydrogen(45 psi) for 18 hours. The reaction mixture was then filtered through apad of diatomaceous earth, and the filtrate was concentrated underreduced pressure and subjected to silica gel chromatography (Gradient:0% to 9% ethyl acetate in petroleum ether). The resulting material wascombined with that from a similar reaction carried out using C3 (1.67 g,3.87 mmol) to afford P1 as a colorless gum. Combined yield: 10.3 g, 23.7mmol, 86%. LCMS m/z 456.1+[M+Na⁺]. ¹H NMR (400 MHz, chloroform-d) δ 7.52(dd, J=8.5, 7.6 Hz, 1H), 7.23-7.17 (m, 2H), 7.16 (s, 1H), 6.83 (dd,J=7.8, 7.8 Hz, 1H), 6.78-6.69 (m, 2H), 4.35-4.10 (br m, 2H), 2.89-2.71(m, 3H), 1.89-1.77 (m, 2H), 1.77-1.63 (m, 2H), 1.47 (s, 9H).

Preparation P2 tert-Butyl4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidine-1-carboxylate(P2)

Step 1. Synthesis of4-bromo-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxole (C4)

To a solution of 3-bromobenzene-1,2-diol (330 g, 1.75 mol) in toluene(1.5 L) were added 1-(4-chloro-2-fluorophenyl)ethanone (316 g, 1.83 mol)and p-toluenesulfonic acid (6.02 g, 35.0 mmol). The reaction apparatuswas fitted with a Dean-Stark trap, and the reaction mixture was heatedat 140° C. for 60 hours, whereupon the solution was concentrated invacuo and purified using silica gel chromatography (Eluent: petroleumether); C4 was obtained as a mixture of yellow oil and solid. Yield: 158g, 460 mmol, 26%. ¹H NMR (400 MHz, chloroform-d): δ 7.54 (dd, J=8.4, 8.4Hz, 1H), 7.17-7.10 (m, 2H), 6.95 (dd, J=7.9, 1.4 Hz, 1H), 6.75 (dd,component of ABX pattern, J=7.8, 1.4 Hz, 1H), 6.70 (dd, component of ABXpattern, J=7.9, 7.9 Hz, 1H), 2.11 (d, J=1.1 Hz, 3H).

Step 2. Synthesis of tert-butyl4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]-3,6-dihydropyridine-1(2H)-carboxylate(C5)

tert-Butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2)-carboxylate(62 g, 200 mmol) and sodium carbonate (100 g, 940 mmol) were added to asolution of C4 (58.0 g, 169 mmol) in 1,4-dioxane (600 mL). Afteraddition of [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)(6.0 g, 8.2 mmol), the reaction mixture was heated to 90° C. and stirredfor 16 hours. Water (500 mL) was then added, and the resulting mixturewas extracted with ethyl acetate (2×500 mL). The combined organic layerswere washed with saturated aqueous sodium chloride solution (2×500 mL),dried over sodium sulfate, filtered, and concentrated in vacuo. Silicagel chromatography (Gradient: 0% to 9% ethyl acetate in petroleum ether)provided C5 as a yellow oil. Yield: 56.0 g, 126 mmol, 75%. ¹H NMR (400MHz, chloroform-d) δ 7.50 (dd, J=8.2, 8.2 Hz, 1H), 7.17-7.09 (m, 2H),6.83-6.77 (m, 2H), 6.74 (dd, component of ABX pattern, J=5.4, 3.6 Hz,1H), 6.39-6.33 (br m, 1H), 4.14-4.08 (m, 2H), 3.70-3.56 (m, 2H),2.66-2.45 (m, 2H), 2.07 (d, J=1.1 Hz, 3H), 1.50 (s, 9H).

Step 3. Synthesis of tert-butyl4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidine-1-carboxylate(P2)

To a solution of C5 (56.0 g, 126 mmol) in methanol (200 mL) was addedtris(triphenylphosphine)rhodium(I) chloride (Wilkinson's catalyst; 8.10g, 8.75 mmol), and the reaction mixture was heated to 50° C. for 18hours under hydrogen (45 psi). It was then cooled to 25° C. and filteredthrough diatomaceous earth. The filtrate was concentrated in vacuo, andpurified twice using silica gel chromatography (First column—Gradient:0% to 9% ethyl acetate in petroleum ether; Second column—Gradient: 0% to2% ethyl acetate in petroleum ether), affording P2 as a yellow solid.Yield: 37.0 g, 82.6 mmol, 66%. LCMS m/z 392.1♦[(M−2-methylprop-1-ene)+H]⁺. ¹H NMR (400 MHz, chloroform-d) δ 7.51 (dd,J=8.3, 8.0 Hz, 1H), 7.17-7.09 (m, 2H), 6.77 (dd, component of ABCpattern, J=7.8, 7.8 Hz, 1H), 6.70 (dd, component of ABC pattern, J=7.7,1.3 Hz, 1H), 6.66 (dd, component of ABC pattern, J=7.8, 1.3 Hz, 1H),4.37-4.13 (br m, 2H), 2.92-2.73 (m, 3H), 2.05 (d, J=1.1 Hz, 3H),1.90-1.63 (m, 4H), 1.49 (s, 9H).

Preparation P34-[(2S)-2-(4-Chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidine,p-toluenesulfonate Salt (P3)

Step 1. Isolation of tert-butyl4-[(2R)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4yl]piperidine-1-carboxylate (C6) and tert-butyl4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidine-1-carboxylate(C7)

Separation of P2 (75.2 g, 168 mmol) into its component enantiomers wascarried out via SFC (supercritical fluid chromatography)_[Column: ChiralTechnologies Chiralpak AD-H, 5 μm; Mobile phase: 4:1 carbondioxide/(2-propanol containing 0.2% 1-aminopropan-2-ol)]. Thefirst-eluting compound was designated as C6, and the second-elutingenantiomer as C7. The indicated absolute configurations were assigned onthe basis of a single-crystal X-ray structure determination carried outon C8, which was derived from C6 (see below).

C6—Yield: 38.0 g, 84.8 mmol, 50%. Retention time 3.64 minutes [Column:Chiral Technologies Chiralpak AD-H, 4.6×250 mm, 5 μm; Mobile phase A:carbon dioxide; Mobile phase B: 2-propanol containing 0.2%1-aminopropan-2-ol; Gradient: 5% B for 1.00 minute, then 5% to 60% Bover 8.00 minutes; Flow rate: 3.0 mL/minute; Back pressure: 120 bar].C7—Yield: 36.8 g, 82.2 mmol, 49%. Retention time 4.19 minutes(Analytical SFC conditions identical to those used for C6).

Step 2. Synthesis of4-[(2)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidine,p-toluenesulfonate Salt (P3)

A solution of C7 (1.62 g, 3.62 mmol) in ethyl acetate (36 mL) wastreated with p-toluenesulfonic acid monohydrate (791 mg, 4.16 mmol) andheated at 45° C. After 23 hours, the reaction mixture was allowed tocool to room temperature and the solid was collected via filtration. Itwas rinsed with a mixture of ethyl acetate and heptane (1:1, 2×15 mL) toafford P3 as a white solid. Yield: 1.37 g, 2.63 mmol, 73%. LCMS m/z348.1♦ [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.53 (v br s, 1H), 8.29 (v brs, 1H), 7.65-7.55 (m, 2H), 7.47 (d, J=8.1 Hz, 2H), 7.35 (dd, J=8.4, 2.0Hz, 1H), 7.11 (d, J=7.8 Hz, 2H), 6.88-6.81 (m, 2H), 6.75-6.68 (m, 1H),3.42-3.33 (m, 2H), 3.11-2.93 (m, 3H), 2.29 (s, 3H), 2.03 (s, 3H),1.98-1.82 (m, 4H).

Conversion of C6 to4-[(2R)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidine,Methanesulfonate Salt (C8) for Determination of Absolute Stereochemistry

p-Toluenesulfonic acid (377 mg, 2.19 mmol) was added to a solution of C6(490 mg, 1.09 mmol) in ethyl acetate (5.5 mL), and the reaction mixturewas stirred at room temperature overnight. After dilution withadditional ethyl acetate, the reaction mixture was washed sequentiallywith aqueous sodium bicarbonate solution, water, and saturated aqueoussodium chloride solution, dried over sodium sulfate, filtered, andconcentrated in vacuo. Yield: 375 mg, 1.08 mmol, 99%. ¹H NMR (400 MHz,methanol-d₄) δ 7.59 (dd, J=8.3. 8.3 Hz, 1H), 7.27 (dd, J=10.9, 2.0 Hz,1H), 7.20 (br dd, J=8.4, 2.1 Hz, 1H), 6.81-6.75 (m, 1H), 6.74-6.67 (m,2H), 3.18-3.09 (m, 2H), 2.88-2.77 (m, 1H), 2.77-2.67 (m, 2H), 2.02 (d,J=0.7 Hz, 3H), 1.85-1.73 (m, 4H).

A 0.1 M solution of this free base(4-[(2R)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidine)in ethyl acetate was prepared and subjected to a salt screen. Only themethanesulfonate salt formation is described here. A mixture ofmethanesulfonic acid (25 μL, 39 μmol) and the solution of substrate (0.1M; 0.25 mL, 25 μmol) was stirred overnight. Sufficient methanol was thenadded to dissolve the solid present, and ethyl acetate (3 mL) was added.The resulting solution was allowed to evaporate slowly, withoutstirring, to afford crystals of C8; one of these was used for the singlecrystal X-ray structure determination described below.

Single-Crystal X-Ray Structural Determination of C8 Single Crystal X-RayAnalysis

Data collection was performed on a Bruker D8 Quest diffractometer atroom temperature. Data collection consisted of omega and phi scans.The structure was solved by intrinsic phasing using SHELX software suitein the orthorhombic class space group P2₁2₁2₁. The structure wassubsequently refined by the full-matrix least squares method. Allnon-hydrogen atoms were found and refined using anisotropic displacementparameters.Formation of the methanesulfonate salt was confirmed via N1_H1X_O4proton transfer.The hydrogen atoms located on nitrogen and oxygen were found from theFourier difference map and refined with distances restrained. Theremaining hydrogen atoms were placed in calculated positions and wereallowed to ride on their carrier atoms. The final refinement includedisotropic displacement parameters for all hydrogen atoms.Analysis of the absolute structure using likelihood methods (Hooft,2008) was performed using PLATON (Spek). The results indicate that theabsolute structure has been correctly assigned; the method calculatesthat the probability that the structure is correct is 100%. The Hooftparameter is reported as 0.02 with an esd of 0.0012 and the Parson'sparameter is reported as 0.07 with an esd of 0.009. The absoluteconfiguration at C7 was confirmed as (R).The asymmetric unit is comprised of one molecule of the protonated freebase of C8 and one molecule of deprotonated methanesulfonic acid. Thefinal R-index was 4.6%. A final difference Fourier revealed no missingor misplaced electron density.Pertinent crystal, data collection, and refinement information issummarized in Table A. Atomic coordinates, bond lengths, bond angles,and displacement parameters are listed in Tables B-D.

SOFTWARE AND REFERENCES

-   SHELXTL, Version 5.1, Bruker AXS, 1997-   PLATON, A. L. Spek, J. Appl. Cryst. 2003, 36, 7-13.-   MERCURY, C. F. Macrae, P. R. Edington, P. McCabe, E. Pidcock, G. P.    Shields, R. Taylor, M.-   Towler, and J. van de Streek, J. Appl. Cryst. 2006, 39, 453-457.-   OLEX2, O. V. Dolomanov, L. J. Bourhis, R. J. Gildea, J. A. K.    Howard, and H. Puschmann, J. Appl. Cryst. 2009, 42, 339-341.-   R. W. W. Hooft, L. H. Straver, and A. L. Spek, J. Appl. Cryst. 2008,    41, 96-103.-   H. D. Flack, Acta Cryst. 1983, A39, 867-881.

TABLE A Crystal data and structure refinement for C8. Empirical formulaC₂₀H₂₃ClFNO₅S Formula weight 443.90 Temperature 296(2) K Wavelength1.54178 Å Crystal system Orthorhombic Space group P2₁2₁2₁ Unit celldimensions a = 6.5348(5) Å α = 90° b = 9.3688(7) Å β = 90° c = 35.214(3)Å γ = 90° Volume 2155.9(3) Å³ Z 4 Density (calculated) 1.368 Mg/m³Absorption coefficient 2.823 mm⁻¹ F(000) 928 Crystal size 0.480 × 0.100× 0.040 mm³ Theta range for data collection 2.509 to 70.483° Indexranges −7 <= h <= 7, −11 <= k <= 8, −42 <= l <= 42 Reflections collected16311 Independent reflections 4035 [R_(int) = 0.0638] Completeness totheta = 67.679° 99.0% Absorption correction Empirical Refinement methodFull-matrix least-squares on F2 Data/restraints/parameters 4035/2/271Goodness-of-fit on F² 0.832 Final R indices [l > 2σ(l)] R1 = 0.0463, wR2= 0.1227 R indices (all data) R1 = 0.0507, wR2 = 0.1294 Absolutestructure parameter −0.003(18) Extinction coefficient 0.0051(6) Largestdiff. peak and hole 0.256 and -0.305 e.Å⁻³

TABLE B Atomic coordinates(×10⁴) and equivalent isotropic displacementparameters (Å² × 10³) for C8. U(eq) is defined as one-third of the traceof the orthogonalized U^(ij) tensor. x y z U(eq) S(1)    3842(2)   9910(1) 5317(1)  57(1) Cl(1)  −1625(2)  −718(1) 6588(1)  80(1) O(1)   6138(4)    3727(3) 6876(1)  53(1) F(1)     639(5)    3071(4) 7503(1) 89(1) O(2)    3445(4)    5043(3) 7117(1)  57(1) O(4)    2909(6)  11013(4) 5082(1)  78(1) O(3)    3708(7)   10299(4) 5708(1)  83(1) N(1)  10461(5)    2909(4) 5493(1)  56(1) C(9)    5652(6)    4826(4) 6629(1) 44(1) C(1)    3361(7)    1662(4) 6697(1)  53(1) C(6)    2957(6)   2523(4) 7012(1)  49(1) C(10)    4075(6)    5613(4) 6776(1)  47(1)C(14)    6628(6)    5138(4) 6294(1)  47(1) O(5)    5833(7)    9578(4)5179(1)  96(1) C(15)    8265(6)    4182(4) 6130(1)  49(1) C(5)   1105(7)    2270(5) 7190(1)  59(1) C(16)    7309(6)    3048(5) 5874(1) 54(1) C(2)    1971(7)     670(4) 6567(1)  55(1) C(4)  −286(7)   1288(5) 7080(1)  64(1) C(7)    4448(6)    3667(4) 7142(1)  52(1)C(13)    5876(8)    6374(5) 6113(1)  60(1) C(11)    3359(7)    6819(4)6602(1)  57(1) C(8)    5296(8)    3485(6) 7537(1)  64(1) C(19)   9905(7)    4976(6) 5902(1)  67(1) C(17)    8902(7)    2063(5) 5702(1) 59(1) C(12)    4316(8)    7178(5) 6263(1)  65(1) C(3)     150(7)    497(4) 6756(1)  56(1) C(18)   11476(7)    3977(6) 5738(1)  73(1)C(20)    2328(14)    8399(7) 5260(2) 117(3)

TABLE C Bond lengths [Å] and angles [°] for C8. S(1)—O(5) 1.423(4)C(4)—C(3) 1.389(6) S(1)—O(3) 1.428(3) C(4)—H(4) 0.9300 S(1)—O(4)1.458(3) C(7)—C(8) 1.506(6) S(1)—C(20) 1.738(6) C(13)—C(12) 1.373(7)Cl(1)—C(3) 1.729(5) C(13)—H(13) 0.9300 O(1)—C(9) 1.385(4) C(11)—C(12)1.388(7) O(1)—C(7) 1.449(4) C(11)—H(11) 0.9300 F(1)—C(5) 1.367(4)C(8)—H(8A) 0.9600 O(2)—C(10) 1.376(4) C(8)—H(8B) 0.9600 O(2)—C(7)1.449(4) C(8)—H(8C) 0.9600 N(1)—C(18) 1.478(6) C(19)—C(18) 1.505(7)N(1)—C(17) 1.486(5) C(19)—H(19A) 0.9700 N(1)—H(1X) 0.99(2) C(19)—H(19B)0.9700 N(1)—H(1Y) 0.97(2) C(17)—H(17A) 0.9700 C(9)—C(10) 1.369(5)C(17)—H(17B) 0.9700 C(9)—C(14) 1.375(5) C(12)—H(12) 0.9300 C(1)—C(2)1.378(6) C(18)—H(18A) 0.9700 C(1)—C(6) 1.395(5) C(18)—H(18B) 0.9700C(1)—H(1) 0.9300 C(20)—H(20A) 0.9600 C(6)—C(5) 1.384(6) C(20)—H(20B)0.9600 C(6)—C(7) 1.519(6) C(20)—H(20C) 0.9600 C(10)—C(11) 1.369(5)O(5)—S(1)—O(3) 116.2(3) C(14)—C(13) 1.409(6) O(5)—S(1)—O(4) 110.1(2)C(14)—C(15) 1.509(5) O(3)—S(1)—O(4) 109.9(2) C(15)—C(16) 1.527(5)O(5)—S(1)—C(20) 107.6(4) C(15)—C(19) 1.531(6) O(3)—S(1)—C(20) 106.6(3)C(15)—H(15) 0.9800 O(4)—S(1)—C(20) 105.9(4) C(5)—C(4) 1.351(7)C(9)—O(1)—C(7) 105.0(3) C(16)—C(17) 1.518(6) C(10)—O(2)—C(7) 105.2(3)C(16)—H(16A) 0.9700 C(18)—N(1)—C(17) 112.3(3) C(16)—H(16B) 0.9700C(18)—N(1)—H(1X) 107(3) C(2)—C(3) 1.372(6) C(17)—N(1)—H(1X) 113(3)C(2)—H(2) 0.9300 C(1)—C(2)—H(2) 120.3 C(18)—N(1)—H(1Y) 113(3)C(5)—C(4)—C(3) 117.5(4) C(17)—N(1)—H(1Y) 103(3) C(5)—C(4)—H(4) 121.2H(1X)—N(1)—H(1Y) 108(4) C(3)—C(4)—H(4) 121.2 C(10)—C(9)—C(14) 124.1(3)O(1)—C(7)—O(2) 105.7(3) C(10)—C(9)—O(1) 109.6(3) O(1)—C(7)—C(8) 108.7(3)C(14)—C(9)—O(1) 126.3(3) O(2)—C(7)—C(8) 108.8(3) C(2)—C(1)—C(6) 121.9(4)O(1)—C(7)—C(6) 108.7(3) C(2)—C(1)—H(1) 119.0 O(2)—C(7)—C(6) 108.6(3)C(6)—C(1)—H(1) 119.0 C(8)—C(7)—C(6) 115.8(3) C(5)—C(6)—C(1) 115.3(4)C(12)—C(13)—C(14) 122.4(4) C(5)—C(6)—C(7) 123.0(3) C(12)—C(13)—H(13)118.8 C(1)—C(6)—C(7) 121.7(4) C(14)—C(13)—H(13) 118.8 C(9)—C(10)—C(11)122.1(4) C(10)—C(11)—C(12) 115.6(4) C(9)—C(10)—O(2) 110.3(3)C(10)—C(11)—H(11) 122.2 C(11)—C(10)—O(2) 127.5(4) C(12)—C(11)—H(11)122.2 C(9)—C(14)—C(13) 113.6(4) C(7)—C(8)—H(8A) 109.5 C(9)—C(14)—C(15)122.1(3) C(7)—C(8)—H(8B) 109.5 C(13)—C(14)—C(15) 124.2(3)H(8A)—C(8)—H(8B) 109.5 C(14)—C(15)—C(16) 110.4(3) C(7)—C(8)—H(8C) 109.5C(14)—C(15)—C(19) 114.1(3) H(8A)—C(8)—H(8C) 109.5 C(16)—C(15)—C(19)108.4(3) H(86)—C(8)—H(8C) 109.5 C(14)—C(15)—H(15) 107.9C(18)—C(19)—C(15) 112.2(4) C(16)—C(15)—H(15) 107.9 C(18)—C(19)—H(19A)109.2 C(19)—C(15)—H(15) 107.9 C(15)—C(19)—H(19A) 109.2 C(4)—C(5)—F(1)117.2(4) C(18)—C(19)—H(19B) 109.2 C(4)—C(5)—C(6) 125.0(4)C(15)—C(19)—H(19B) 109.2 F(1)—C(5)—C(6) 117.9(4) H(19A)—C(19)—H(19B)107.9 C(17)—C(16)—C(15) 112.2(3) N(1)—C(17)—C(16) 110.1(3)C(17)—C(16)—H(16A) 109.2 N(1)—C(17)—H(17A) 109.6 C(15)—C(16)—H(16A)109.2 C(16)—C(17)—H(17A) 109.6 C(17)—C(16)—H(16B) 109.2N(1)—C(17)—H(17B) 109.6 C(15)—C(16)—H(16B) 109.2 C(16)—C(17)—H(17B)109.6 H(16A)—C(16)—H(16B) 107.9 H(17A)—C(17)—H(17B) 108.2 C(3)—C(2)—C(1)119.4(4) C(13)—C(12)—C(11) 122.1(4) C(3)—C(2)—H(2) 120.3C(13)—C(12)—H(12) 118.9 C(1)—C(2)—H(2) 120.3 C(11)—C(12)—H(12) 118.9C(2)—C(3)—C(4) 120.8(4) H(18A)—C(18)—H(18B) 108.2 C(2)—C(3)—Cl(1)119.6(3) S(1)—C(20)—H(20A) 109.5 C(4)—C(3)—Cl(1) 119.6(3)S(1)—C(20)—H(20B) 109.5 N(1)—C(18)—C(19) 109.9(3) H(20A)—C(20)—H(20B)109.5 N(1)—C(18)—H(18A) 109.7 S(1)—C(20)—H(20C) 109.5 C(19)—C(18)—H(18A)109.7 H(20A)—C(20)—H(20C) 109.5 N(1)—C(18)—H(18B) 109.7H(20B)—C(20)—H(20C) 109.5 C(19)—C(18)—H(18B) 109.7Symmetry transformations used to generate equivalent atoms.

TABLE D Anisotropic displacement parameters (Å² × 10³) for C8. Theanisotropic displacement factor exponent takes the form: −2π²[h²a*²U¹¹ + . . . + 2 h k a* b* U¹²]. U¹¹ U²² U³³ U²³ U¹³ U¹² S(1) 73(1)48(1) 48(1) −2(1)   7(1) −1(1) Cl(1) 81(1) 78(1) 81(1) −8(1)   1(1)−8(1) O(1) 54(1) 50(1) 56(1) 14(1)  10(1) 17(1) F(1) 83(2) 103(2)  79(2)−40(2)  38(2) −6(2) O(2) 66(2) 49(1) 54(1) 2(1) 11(1) 18(1) O(4) 87(2)84(2) 64(2) 19(2)  17(2) 21(2) O(3) 122(3)  80(2) 47(1) −3(1)   7(2)−13(2)  N(1) 47(2) 73(2) 48(2) 7(2)  3(1) 11(2) C(9) 51(2) 38(2) 44(2)2(1) −7(1)  2(2) C(1) 63(2) 46(2) 50(2) 5(2) 21(2) 13(2) C(6) 55(2)47(2) 45(2) 5(1) 11(2) 19(2) C(10) 55(2) 39(2) 46(2) −5(1)  −4(2)  6(2)C(14) 54(2) 46(2) 42(2) 0(1) −9(2) −5(2) O(5) 88(2) 88(3) 113(3) −24(2)  13(2) 21(2) C(15) 47(2) 61(2) 40(2) 3(2) −3(1) −2(2) C(5) 60(2)62(2) 54(2) −6(2)  19(2) 13(2) C(16) 43(2) 53(2) 65(2) −4(2)   8(2)−6(2) C(2) 72(3) 49(2) 45(2) 2(2) 16(2) 14(2) C(4) 57(2) 68(3) 65(2)−3(2)  23(2)  6(2) C(7) 54(2) 50(2) 51(2) 7(2) 12(2) 16(2) C(13) 81(3)54(2) 46(2) 9(2) −4(2)  4(2) C(11) 70(3) 46(2) 54(2) −8(2)  −14(2) 17(2) C(8) 69(3) 71(3) 51(2) 4(2)  4(2) 15(2) C(19) 54(2) 78(3) 70(3)−13(2)   2(2) −25(2)  C(17) 54(2) 57(2) 67(2) −3(2)   8(2)  3(2) C(12)96(3) 43(2) 56(2) 5(2) −14(2)  13(2) C(3) 64(2) 52(2) 52(2) 4(2)  2(2)14(2) C(18) 43(2) 103(4)  73(3) 7(3)  3(2) −18(2)  C(20) 153(7)  87(4)110(5)  −14(4)  −6(5) −57(5) 

Preparation of P3, di-p-toluoyl-L-tartrate Salt4-[(2S)-2-(4-Chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidine,di-p-toluoyl-L-tartrate Salt (P3, di-p-toluoyl-L-tartrate Salt)

A solution of C13, free base (519 mg, 1.49 mmol) anddi-p-toluoyl-L-tartaric acid (278 mg, 0.719 mmol) in acetonitrile (7.5mL) was stirred at 50° C. for 1.5 hours. The mixture was allowed to coolto room temperature at 0.2° C./minute. After 15 hours at roomtemperature, the mixture was heated to 65° C. and charged withacetonitrile (15 mL). The mixture was allowed to cool to roomtemperature at 0.2° C./minute. After 15 hours at room temperature, themixture was heated to 54° C. After 3 hours, the solid was collected byfiltration, and dried in a vacuum oven at 35° C. under nitrogen,providing P3, di-p-toluoyl-L-tartrate salt as a white solid (217 mg,0.296 mmol, 20%, 82% ee).

A solution of P3, di-p-toluoyl-L-tartrate salt (217 mg, 0.296 mmol, 82%ee) in acetonitrile (8.0 mL) at 50° C. was allowed to cool to roomtemperature at 0.2° C./minute. After 15 hours, the solid was collectedby filtration, and dried in a vacuum oven at 35° C. under nitrogen,providing P3, di-p-toluoyl-L-tartrate salt as a white solid (190 mg,0.259 mmol, 88%, 88% ee). LCMS m/z 348.1♦ [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆) δ 8.9-8.5 (br s, 2H), 7.79 (d, J=8.1 Hz, 4H), 7.64-7.54 (m,2H), 7.34 (dd, J=8.4, 2.1 Hz, 1H), 7.26 (d, J=8.0 Hz, 4H), 6.87-6.78 (m,2H), 6.69 (dd, J=6.7, 2.5 Hz, 1H), 5.58 (s, 2H), 3.37-3.28 (m, 2H,assumed; partially obscured by water peak), 3.05-2.89 (m, 3H), 2.33 (s,6H), 2.02 (s, 3H), 1.92-1.80 (m, 4H). Retention time: Peak 1 (4.97minutes, minor) and Peak 2 (5.31 minutes, Major) {Column: Chiralpak IC-U3.0×50 mm, 1.6 μm; Mobile phase A: carbon dioxide; Mobile phase B: 0.1%isopropylamine in methanol; Gradient: 10% B for 5.00 minutes, then 45% Bfor 0.6 minutes; Flow rate: 1.7 mL/minute; Back pressure: 130 bar}.

Preparation P4 tert-Butyl4-[2-(4-cyano-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidine-1-carboxylate(P4)

A suspension of P2 (2.00 g, 4.46 mmol), zinc cyanide (734 mg, 6.25 mol),zinc (70.1 mg, 1.07 mmol), 1,1′-bis(diphenylphosphino)ferrocene (dppf;198 mg, 0.357 mmol) and tris(dibenzylideneacetone)dipalladium(0) (164mg, 0.179 mmol) in N,N-dimethylacetamide (20 mL) was stirred at 120° C.for 16 hours, whereupon it was filtered. The filtrate was mixed withwater (50 mL) and extracted with ethyl acetate (3×50 mL); the combinedorganic layers were then washed sequentially with water (30 mL) and withsaturated aqueous sodium chloride solution (20 mL), and concentrated invacuo. Silica gel chromatography (Gradient: 0% to 30% ethyl acetate inpetroleum ether) afforded a solid, which was treated with acetonitrile(15 mL) and water (15 mL) and subjected to lyophilization. This providedP4 as a light yellow solid. Yield: 1.17 g, 2.67 mmol, 60%. LCMS m/z461.3 [M+Na⁺]. ¹H NMR (400 MHz, chloroform-d) 7.71 (dd, J=7.7, 7.6 Hz,1H), 7.45 (dd, J=8.0, 1.6 Hz, 1H), 7.42 (dd, J=10.0, 1.5 Hz, 1H), 6.79(dd, component of ABC pattern, J=7.7, 7.6 Hz, 1H), 6.72 (dd, componentof ABC pattern, J=7.8, 1.3 Hz, 1H), 6.68 (dd, component of ABC pattern,J=7.8, 1.3 Hz, 1H), 4.37-4.14 (br m, 2H), 2.91-2.73 (m, 3H), 2.07 (d,J=1.1 Hz, 3H), 1.89-1.62 (m, 4H), 1.49 (s, 9H).

Preparations P5 and P6 4-Bromo-2-phenyl-1,3-benzodioxole, ENT-1 (P5) and4-Bromo-2-phenyl-1,3-benzodioxole, ENT-2 (P6)

Step 1. Synthesis of 2-bromo-6-[hydroxy(phenyl)methyl]phenol (C9)

Phenyllithium (1.9 M solution in 1-butoxybutane; 78.5 mL, 149 mmol) wasslowly added to a −70° C. solution of 3-bromo-2-hydroxybenzaldehyde(10.0 g, 49.7 mmol) in tetrahydrofuran (70 mL), at a rate thatmaintained the reaction temperature below −60° C. The resultingsuspension was stirred at −70° C. for 1 hour, and then allowed to warmto room temperature overnight, whereupon it was poured into a 0° C.aqueous ammonium chloride solution (30 mL). This mixture was extractedwith ethyl acetate (3×30 mL), and the combined organic layers werewashed with saturated aqueous sodium chloride solution (30 mL), driedover sodium sulfate, filtered, and concentrated in vacuo. Silica gelchromatography (Gradient: 0% to 5% ethyl acetate in petroleum ether)provided C9 as a yellow solid. Yield: 6.11 g, 21.9 mmol, 44%. ¹H NMR(400 MHz, chloroform-d) δ 7.45-7.28 (m, 6H), 7.22-7.18 (m, 1H), 7.06 (brd, J=7.7 Hz, 1H), 6.77 (dd, J=7.9, 7.8 Hz, 1H), 6.06 (br s, 1H), 2.89(br s, 1H).

Step 2. Synthesis of 4-bromo-2-phenyl-1,3-benzodioxole (C10)

To a solution of C9 (6.11 g, 21.9 mmol) in methanol (370 mL) was added asolution of sodium periodate (11.7 g, 54.7 mmol) in water (175 mL). Thereaction mixture was stirred at 30° C. for 40 hours, whereupon most ofthe methanol was removed via concentration in vacuo. The resultingmixture was extracted with dichloromethane (5×100 mL), and the combinedorganic layers were washed sequentially with aqueous sodium sulfitesolution (100 mL) and saturated aqueous sodium chloride solution (100mL), dried over sodium sulfate, filtered, and concentrated under reducedpressure. Chromatography on silica gel (Eluent: petroleum ether)provided C10 as a colorless oil. Yield: 4.50 g, 16.2 mmol, 74%. LCMS m/z278.5 (bromine isotope pattern observed) [M+H]⁺. ¹H NMR (400 MHz,chloroform-d) δ 7.62-7.57 (m, 2H), 7.49-7.43 (m, 3H), 7.04 (s, 1H), 7.00(dd, J=8.0, 1.4 Hz, 1H), 6.79 (dd, component of ABX pattern, J=7.8, 1.4Hz, 1H), 6.75 (dd, component of ABX pattern, J=7.9, 7.8 Hz, 1H).

Step 3. Isolation of 4-bromo-2-phenyl-1,3-benzodioxole, ENT-1 (P5) and4-bromo-2-phenyl-1,3-benzodioxole, ENT-2 (P6)

The enantiomers comprising C10 (5.00 g, 18.0 mmol) were separated usingSFC [Column: Chiral Technologies ChiralCel OD, 10 μm; Mobile phase: 3:1carbon dioxide/(methanol containing 0.1% ammonium hydroxide)]. Thefirst-eluting enantiomer was designated as ENT-1 (P5), and thesecond-eluting enantiomer as ENT-2 (P6); both were obtained as yellowoils.

P5 Yield: 2.20 g, 7.94 mmol, 44%. LCMS m/z 277.0 (bromine isotopepattern observed) [M+H]⁺. ¹H NMR (400 MHz, chloroform-d) δ 7.63-7.55 (m,2H), 7.51-7.42 (m, 3H), 7.04 (s, 1H), 7.00 (dd, J=8.0, 1.3 Hz, 1H), 6.80(dd, component of ABX pattern, J=7.8, 1.4 Hz, 1H), 6.75 (dd, componentof ABX pattern, J=7.9, 7.8 Hz, 1H). Retention time 3.28 minutes (Column:Chiral Technologies ChiralCel OD-H, 4.6×150 mm, 5 μm; Mobile phase A:carbon dioxide; Mobile phase B: methanol containing 0.05% diethylamine;Gradient: 5% to 40% B over 5.5 minutes; Flow rate: 2.5 mL/minute).

P6 Yield: 2.00 g, 7.22 mmol, 40%. LCMS m/z 276.9 (bromine isotopepattern observed) [M+H]⁺. ¹H NMR (400 MHz, chloroform-d) δ 7.63-7.55 (m,2H), 7.50-7.42 (m, 3H), 7.04 (s, 1H), 7.00 (dd, J=8.0, 1.4 Hz, 1H), 6.80(dd, component of ABX pattern, J=7.8, 1.4 Hz, 1H), 6.75 (dd, componentof ABX pattern, J=7.9, 7.9 Hz, 1H). Retention time 3.73 minutes(Analytical conditions identical to those used for P5).

Preparation P7 tert-Butyl4-[2-(5-chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidine-1-carboxylate(P7)

Step 1. Synthesis of2-(4-bromo-2-methyl-1,3-benzodioxol-2-yl)-5-chloropyridine (C11)

A mixture of 5-chloro-2-ethynylpyridine (1.80 g, 13.1 mmol),3-bromobenzene-1,2-diol (2.47 g, 13.1 mmol), and trirutheniumdodecacarbonyl (167 mg, 0.261 mmol) in toluene (25 mL) was degassed for1 minute and then heated at 100° C. for 16 hours. The reaction mixturewas diluted with ethyl acetate (30 mL) and filtered through a pad ofdiatomaceous earth; the filtrate was concentrated in vacuo and purifiedusing silica gel chromatography (Gradient: 0% to 1% ethyl acetate inpetroleum ether) to provide C11 as a yellow oil. Yield: 1.73 g, 5.30mmol, 40%. LCMS m/z 325.6 (bromine-chlorine isotope pattern observed)[M+H]⁺. ¹H NMR (400 MHz, chloroform-d) δ 8.63 (dd, J=2.4, 0.7 Hz, 1H),7.71 (dd, component of ABX pattern, J=8.4, 2.4 Hz, 1H), 7.60 (dd,component of ABX pattern, J=8.4, 0.7 Hz, 1H), 6.97 (dd, J=8.0, 1.4 Hz,1H), 6.76 (dd, component of ABX pattern, J=7.8, 1.4 Hz, 1H), 6.72 (dd,component of ABX pattern, J=8.0, 7.8 Hz, 1H), 2.10 (s, 3H).

Step 2. Synthesis of tert-butyl4-[2-(5-chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]-3,6-dihydropyridine-1(2H)-carboxylate(C12)

[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (388 mg,0.530 mmol) was added to a suspension of C11 (1.73 g, 5.30 mmol),tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate(1.64 g, 5.30 mmol), and cesium carbonate (5.18 g, 15.9 mmol) in1,4-dioxane (35 mL) and water (6 mL). The reaction mixture was stirredat 90° C. for 4 hours, whereupon it was diluted with ethyl acetate (30mL) and water (5 mL). The organic layer was concentrated in vacuo andthe residue was subjected to silica gel chromatography (Gradient: 0% to5% ethyl acetate in petroleum ether), affording C12 as a yellow gum.Yield: 1.85 g, 4.31 mmol, 81%. LCMS m/z 451.0♦ [M+Na⁺]. ¹H NMR (400 MHz,chloroform-d) δ 8.62 (dd, J=2.5, 0.8 Hz, 1H), 7.69 (dd, component of ABXpattern, J=8.4, 2.4 Hz, 1H), 7.57 (dd, component of ABX pattern, J=8.4,0.8 Hz, 1H), 6.84-6.79 (m, 2H), 6.78-6.73 (m, 1H), 6.39-6.33 (br m, 1H),4.13-4.07 (m, 2H), 3.68-3.58 (m, 2H), 2.60-2.51 (br m, 2H), 2.07 (s,3H), 1.49 (s, 9H).

Step 3. Synthesis of tert-butyl4-[2-(5-chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidine-1-carboxylate(P7)

A solution of C12 (2.61 g, 6.08 mmol) andtris(triphenylphosphine)rhodium(I) chloride (Wilkinson's catalyst; 563mg, 0.608 mmol) in methanol (100 mL) was degassed under vacuum and thenpurged with hydrogen; this evacuation-purge cycle was carried out atotal of three times. The reaction mixture was then stirred at 60° C.under hydrogen (50 psi) for 16 hours, whereupon it was filtered. Thefiltrate was concentrated in vacuo, and the residue was purified usingsilica gel chromatography (Gradient: 0% to 10% ethyl acetate inpetroleum ether); the resulting material was combined with material froma similar hydrogenation carried out on C12 (110 mg, 0.256 mmol) toprovide P7 as a light-yellow gum. Combined yield: 2.05 g, 4.76 mmol,75%. LCMS m/z 431.3♦ [M+H]⁺. ¹H NMR (400 MHz, chloroform-d) δ 8.62 (d,J=2.3 Hz, 1H), 7.69 (dd, component of ABX pattern, J=8.4, 2.4 Hz, 1H),7.57 (d, half of AB quartet, J=8.4 Hz 1H), 6.79 (dd, component of ABCpattern, J=7.8, 7.7 Hz, 1H), 6.72 (dd, component of ABC pattern, J=7.8,1.3 Hz, 1H), 6.68 (br d, component of ABC pattern, J=7.9 Hz, 1H),4.32-4.12 (br m, 2H), 2.91-2.73 (m, 3H), 2.05 (s, 3H), 1.90-1.62 (m,4H), 1.48 (s, 9H).

Preparations P8 and P9 tert-Butyl4-[2-(5-chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidine-1-carboxylate,ENT-1 (P8) and tert-Butyl4-[2-(5-chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidine-1-carboxylate,ENT-2 (P9)

Separation of P7 (500 mg, 1.16 mmol) into its component enantiomers waseffected using SFC {Column: Phenomenex Lux Amylose-1, 5 μm; Mobilephase: 9:1 carbon dioxide/[2-propanol containing 0.2% (7 M ammonia inmethanol)]}. The first-eluting enantiomer was designated as ENT-1 (P8),and the second-eluting enantiomer as ENT-2 (P9).

P8 Yield: 228 mg, 0.529 mmol, 46%. Retention time 4.00 minutes {Column:Phenomenex Lux Amylose-1, 4.6×250 mm, 5 μm; Mobile phase A: carbondioxide; Mobile phase B: [2-propanol containing 0.2% (7 M ammonia inmethanol)]; Gradient: 5% B for 1.00 minute, then 5% to 60% B over 8.00minutes; Flow rate: 3.0 mL/minute; Back pressure: 120 bar}.

P9 Yield: 229 mg, 0.531 mmol, 46%. Retention time 4.50 minutes(Analytical conditions identical to those used for P8).

Preparation P10{4-[2-(4-Chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}aceticacid (P10)

Step 1. Synthesis of4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidine,p-toluenesulfonate Salt (C13)

A solution of P2 (5.0 g, 11 mmol) and p-toluenesulfonic acid (4.81 g,27.9 mmol) in ethyl acetate (100 mL) was stirred at 60° C. for 2 hours,whereupon it was concentrated in vacuo to afford C13 as a yellow gum.This material was taken directly into the following step. LCMS m/z347.9♦ [M+H]⁺.

Step 2. Synthesis of ethyl{4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}acetate(C14)

Potassium carbonate (7.71 g, 55.8 mmol) and ethyl bromoacetate (1.86 g,11.2 mmol) were added to a solution of C13 (from the previous step; ≤11mmol) in acetonitrile (150 mL), and the reaction mixture was stirred at55° C. for 16 hours. It was then filtered, and the filtrate wasconcentrated in vacuo and purified using silica gel chromatography(Gradient: 0% to 30% ethyl acetate in petroleum ether) to afford C14 asa yellow gum. By ¹H NMR analysis, this material was not entirely pure.Yield: 3.57 g, 8.23 mmol, 75% over 2 steps. ¹H NMR (400 MHz,chloroform-d), C14 peaks only: δ 7.52 (dd, J=8.4, 8.0 Hz, 1H), 7.17-7.07(m, 2H), 6.77 (dd, component of ABC pattern, J=7.8, 7.8 Hz, 1H),6.72-6.67 (m, 2H), 4.21 (q, J=7.1 Hz, 2H), 3.27 (s, 2H), 3.07 (m, 2H),2.70 (tt, J=12.1, 3.8 Hz, 1H), 2.35 (ddd, J=11.5, 11.5, 2.7 Hz, 2H),2.04 (d, J=1.1 Hz, 3H), 2.02-1.76 (m, 4H), 1.29 (t, J=7.1 Hz, 3H).

Step 3. Synthesis of{4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}aceticAcid (P10)

A solution of C14 (3.57 g, 8.23 mmol) and aqueous sodium hydroxidesolution (3 M; 13.7 mL, 41.1 mmol) in a mixture of methanol (80 mL) andtetrahydrofuran (40 mL) was stirred at 25° C. for 16 hours. Afterremoval of solvents in vacuo, the aqueous residue was acidified to pH 7by addition of 1 M hydrochloric acid, and then extracted with a mixtureof dichloromethane and methanol (10:1, 2×100 mL). The combined organiclayers were dried over sodium sulfate, filtered, and concentrated underreduced pressure to provide P10 as a yellow solid. Yield: 2.95 g, 7.27mmol, 88%. LCMS m/z 406.2♦ [M+H]⁺. ¹H NMR (400 MHz, methanol-d₄) δ 7.61(dd, J=8.3, 8.3 Hz, 1H), 7.29 (dd, J=10.9, 2.0 Hz, 1H), 7.22 (ddd,J=8.4, 2.0, 0.8 Hz, 1H), 6.82 (dd, component of ABC pattern, J=8.3, 7.1Hz, 1H), 6.78-6.72 (m, 2H), 3.65-3.54 (br m, 2H), 3.51 (s, 2H),3.04-2.88 (m, 3H), 2.23-2.07 (m, 2H), 2.07-1.93 (m, 2H), 2.04 (d, J=1.1Hz, 3H).

Preparation P11 Methyl2-(chloromethyl)-1-(2-methoxyethyl)-1H-benzimidazole-6-carboxylate (P11)

Step 1. Synthesis of methyl 3-[(2-methoxyethyl)amino]-4-nitrobenzoate(C15)

To a colorless solution of methyl 3-fluoro-4-nitrobenzoate (50 g, 250mmol) in tetrahydrofuran (400 mL) was added triethylamine (40.7 g, 402mmol, 55.8 mL) followed by addition of 2-methoxyethanamine (30.2 g, 402mmol) in tetrahydrofuran (100 mL), drop-wise, at room temperature. Theresultant yellow solution was stirred at 55° C. for 18 hours. Thesolution was cooled to room temperature and concentrated under reducedpressure to remove tetrahydrofuran. The resultant yellow solid wasdissolved in ethyl acetate (800 mL) and washed with saturated aqueousammonium chloride solution (250 mL). The aqueous phase was separated andextracted with ethyl acetate (200 mL). The combined organic layers werewashed with saturated aqueous sodium chloride solution (3×250 mL), driedover sodium sulfate, filtered, and concentrated under reduced pressureto yield C15 (60.2 g, 94%) as a yellow solid. ¹H NMR (600 MHz,chloroform-d) δ 8.23 (d, 1H), 8.17 (br s, 1H), 7.58 (d, 1H), 7.25 (dd,1H), 3.95 (s, 3H), 3.69-3.73 (m, 2H), 3.56 (m, 2H), 3.45 (s, 3H); LCMSm/z 255.4 [M+H]⁺.

Step 2. Synthesis of methyl 4-amino-3-[(2-methoxyethyl)amino]benzoate(C16)

To solution of C15 (30 g, 118 mmol) in methanol (500 mL) was added Pd/C(10 g, 94 mmol). This reaction was stirred at room temperature under 15psi hydrogen for 18 hours. The black suspension was filtered throughdiatomaceous earth and the filter cake was washed with methanol (500mL). The combined filtrates were concentrated in vacuo to give C16 (26.5g, quantitative) as a brown oil, which solidified on standing. ¹H NMR(400 MHz, chloroform-d) δ 7.48 (dd, 1H), 7.36 (d, 1H), 6.69 (d, 1H),3.87 (s, 3H), 3.77 (br s, 2H), 3.68 (t, 2H), 3.41 (s, 3H), 3.32 (t, 2H);LCMS m/z 224.7 [M+H]⁺.

Step 3. Synthesis of methyl2-(chloromethyl)-1-(2-methoxyethyl)-1H-benzimidazole-6-carboxylate (P11)

To a solution of C16 (5.00 g, 22.3 mmol) in tetrahydrofuran (100 mL) wasadded 2-chloro-1,1,1-trimethoxyethane (3.31 mL, 24.6 mmol), followed byp-toluenesulfonic acid monohydrate (84.8 mg, 0.446 mmol). The reactionmixture was heated at 45° C. for 5 hours, whereupon it was concentratedin vacuo; the residual oil was dissolved in ethyl acetate (10 mL) andheated until a solution formed. This was slowly stirred while cooling toroom temperature overnight. The precipitate was collected via filtrationand washed with heptane to afford P11 as a gray solid. Yield: 5.73 g,20.3 mmol, 91%. ¹H NMR (600 MHz, chloroform-d) δ 8.12 (br s, 1H), 8.01(br d, J=8.6 Hz, 1H), 7.79 (d, J=8.4 Hz, 1H), 4.96 (s, 2H), 4.52 (t,J=5.1 Hz, 2H), 3.96 (s, 3H), 3.74 (t, J=5.1 Hz, 2H), 3.28 (s, 3H).

Step 4. Synthesis of methyl2-(chloromethyl)-1-(2-methoxyethyl)-1H-benzimidazole-6-carboxylate,Hydrochloride Salt (P11, HCl Salt)

A solution of C16 (5.0 g, 24 mmol) in 1,4-dioxane (100 mL) was heated to100° C., a solution of chloroacetic anhydride (4.1 g, 24.5 mmol) in1,4-dioxane (60 mL) was added via addition funnel over a period of 10hours, and the reaction mixture was stirred for another 12 hours at 100°C. The following day, the reaction was cooled to room temperature andthe 1,4-dioxane was removed under reduced pressure. The crude reactionmixture was dissolved in ethyl acetate and washed with saturated aqueoussodium bicarbonate solution. The ethyl acetate layer was separated,dried over sodium sulfate, and filtered. A solution of 4 M hydrogenchloride in 1,4-dioxane (1.1 equiv.) was added to the ethyl acetatesolution with constant stirring. The hydrochloride salt of P11precipitated out as a pale yellow solid. The suspension was stirred for1 hour and the hydrochloride salt of P11 was then collected byfiltration to give a yellow solid (6.1 g, 86%). ¹H NMR (600 MHz, CD30D)68.64 (s, 1H), 8.30 (d, 1H), 7.92 (d, 1H), 5.32 (s, 2H), 4.84 (m, 2H),3.99 (s, 3H), 3.83 (t, 2H), 3.31 (s, 3H). LCMS m/z 283.2 [M+H]⁺.

Preparation P12 Methyl1-(2-methoxyethyl)-2-(piperazin-1-ylmethyl)-1H-benzimidazole-6-carboxylate(P12)

Step 1. Synthesis of methyl2-{[4-(tert-butoxycarbonyl)piperazin-1-yl]methyl}-1-(2-methoxyethyl)-1H-benzimidazole-6-carboxylate(C17)

Compound P11 (1.59 g, 5.62 mmol) was added to a 15° C. mixture oftert-butyl piperazine-1-carboxylate (1.00 g, 5.37 mmol) and potassiumcarbonate (2.97 g, 21.5 mmol) in acetonitrile (15 mL), and the reactionmixture was stirred at 55° C. for 12 hours. It was then combined with asimilar reaction carried out using P11 and tert-butylpiperazine-1-carboxylate (200 mg, 1.07 mmol), and the mixture wasfiltered. After the filtrate had been concentrated in vacuo, the residuewas purified via chromatography on silica gel (Gradient: 0% to 60% ethylacetate in petroleum ether) to provide C17 as a pale yellow solid.Combined yield: 2.30 g, 5.32 mmol, 83%. LCMS m/z 433.0 [M+H]⁺. ¹H NMR(400 MHz, chloroform-d) δ 8.12 (d, J=1.5 Hz, 1H), 7.96 (dd, J=8.4, 1.5Hz, 1H), 7.73 (d, J=8.5 Hz, 1H), 4.58 (t, J=5.4 Hz, 2H), 3.95 (s, 3H),3.89 (s, 2H), 3.73 (t, J=5.4 Hz, 2H), 3.46-3.37 (br m, 4H), 3.28 (s,3H), 2.54-2.44 (br m, 4H), 1.45 (s, 9H).

Step 2. Synthesis of methyl1-(2-methoxyethyl)-2-(piperazin-1-ylmethyl)-1H-benzimidazole-6-carboxylate(P12)

To a solution of C17 (2.30 g, 5.32 mmol) in dichloromethane (80 mL) wasadded a solution of hydrogen chloride in ethyl acetate (20 mL). Thereaction mixture was stirred at 20° C. for 2 hours, whereupon it wasconcentrated in vacuo. The residue was diluted with water (20 mL),adjusted to a pH of 9 to 10 by addition of saturated aqueous sodiumbicarbonate solution, and extracted with a mixture of ethyl acetate andmethanol (10:1, 15×50 mL). The combined organic layers were dried oversodium sulfate, filtered, and concentrated in vacuo to afford P12 as apale yellow solid. Yield: 1.68 g, 5.05 mmol, 95%. LCMS m/z 332.8 [M+H]⁺.¹H NMR (400 MHz, chloroform-d) δ 8.13 (br s, 1H), 7.96 (br d, J=8.5 Hz,1H), 7.72 (d, J=8.5 Hz, 1H), 4.59 (t, J=5.5 Hz, 2H), 3.95 (s, 3H), 3.86(s, 2H), 3.75 (t, J=5.5 Hz, 2H), 3.29 (s, 3H), 2.87 (t, J=4.8 Hz, 4H),2.50 (br m, 4H).

Preparation P136-Bromo-2-(chloromethyl)-1-(2-methoxyethyl)-1H-imidazo[4,5-b]pyridine(P13)

Step 1. Synthesis of 5-bromo-N-(2-methoxyethyl)-2-nitropyridin-3-amine(C18)

A solution of 5-bromo-3-fluoro-2-nitropyridine (400 mg, 1.81 mmol) and2-methoxyethanamine (408 mg, 5.43 mmol) in tetrahydrofuran (10 mL) wasstirred at 25° C. for 2 hours, whereupon it was diluted with ethylacetate (100 mL) and washed with water (50 mL). The organic layer waswashed with saturated aqueous sodium chloride solution (50 mL), driedover magnesium sulfate, filtered, and concentrated to afford C18 as ayellow solid. Yield: 430 mg, 1.56 mmol, 86%.

Step 2. Synthesis of 5-bromo-N³-(2-methoxyethyl)pyridine-2,3-diamine(C19)

A solution of C18 (430 mg, 1.56 mmol), ammonium chloride (833 mg, 15.6mmol), and iron powder (870 mg, 15.6 mmol) in a mixture of methanol (10mL) and water (2 mL) was stirred at 80° C. for 30 minutes. The resultingsuspension was poured into water (50 mL) and extracted with ethylacetate (2×50 mL); the combined organic layers were dried over magnesiumsulfate, filtered, and concentrated to provide C19 as a brown solid.Yield: 350 mg, 1.42 mmol, 91%. ¹H NMR (400 MHz, chloroform-d) δ 7.63 (d,J=2.1 Hz, 1H), 6.88 (d, J=2.0 Hz, 1H), 4.33-4.19 (br s, 2H), 3.65 (dd,J=5.6, 4.6 Hz, 2H), 3.40 (s, 3H), 3.22 (br t, J=5 Hz, 2H).

Step 3. Synthesis of6-bromo-2-(chloromethyl)-1-(2-methoxyethyl)-1H-imidazo[4,5-b]pyridine(P13)

A solution of C19 (400 mg, 1.63 mmol) in 1,4-dioxane (8 mL) was treatedwith chloroacetyl chloride (0.284 mL, 3.57 mmol) and stirred at roomtemperature until LCMS analysis indicated complete conversion of C19 tothe intermediate amide. After removal of the 1,4-dioxane in vacuo, theresidue was dissolved in trifluoroacetic acid (8 mL) and heated at 80°C. for 18 hours, whereupon the reaction mixture was cooled to roomtemperature and concentrated under reduced pressure. The resulting oilwas dissolved in ethyl acetate (50 mL) and neutralized by addition ofsaturated aqueous sodium bicarbonate solution. The aqueous layer wasextracted with ethyl acetate (20 mL), and the combined organic layerswere dried over sodium sulfate, filtered, and concentrated in vacuo.Silica gel chromatography (Gradient: 0% to 80% ethyl acetate in heptane)afforded P13 as a solid. Yield: 176 mg, 0.578 mmol, 35%. LCMS m/z 306.1(bromine-chlorine isotope pattern observed) [M+H]⁺. ¹H NMR (600 MHz,chloroform-d) δ 8.58 (br s, 1H), 7.89 (br s, 1H), 4.92 (s, 2H), 4.44 (t,J=5.0 Hz, 2H), 3.71 (t, J=5.0 Hz, 2H), 3.28 (s, 3H).

Preparation P14 Methyl2-{[4-(2,3-dihydroxyphenyl)piperidin-1-yl]methyl}-1-(2-methoxyethyl)-1H-benzimidazole-6-carboxylate(P14)

Step 1. Synthesis of[(3-bromobenzene-1,2-diyl)bis(oxymethanediyloxyethane-2,1-diyl)]bis(trimethylsilane)(C20)

This reaction was carried out in two batches of identical scale.N,N-Diisopropylethylamine (37.8 mL, 217 mmol) was added drop-wise to asolution of 3-bromobenzene-1,2-diol (10.0 g, 52.9 mmol) intetrahydrofuran (300 mL). After the mixture had been stirred for 10minutes at 20° C., [2-(chloromethoxy)ethyl](trimethyl)silane (19.2 mL,108 mmol) was added drop-wise over 5 minutes, and stirring was continuedfor 16 hours at room temperature (18° C.). N,N-Diisopropylethylamine(27.6 mL, 158 mmol) was again added, followed by drop-wise addition of[2-(chloromethoxy)ethyl](trimethyl)silane (14.0 mL, 79.1 mmol) at roomtemperature (18° C.). After another 2.5 hours at room temperature, thereaction mixture was filtered, and the filtrate was concentrated invacuo. At this point, the crude products from the two batches werecombined and purified using silica gel chromatography (Gradient: 0% to7% ethyl acetate in petroleum ether), to afford C20 as a colorless oil.By ¹H NMR analysis, this material was not entirely pure. Combined yield:22.9 g, 50.9 mmol, 48%. ¹H NMR (400 MHz, chloroform-d), C20 peaks only:δ 7.19 (dd, J=8.1, 1.5 Hz, 1H), 7.12 (dd, J=8.3, 1.4 Hz, 1H), 6.90 (dd,J=8.2. 8.2 Hz, 1H), 5.26-5.19 (m, 4H), 4.00-3.92 (m, 2H), 3.80-3.73 (m,2H), 1.00-0.91 (m, 4H), 0.03 (s, 9H), 0.00 (s, 9H).

Step 2. Synthesis of tert-butyl4-(2,3-bis{[2-(trimethylsilyl)ethoxy]methoxy}phenyl)-3,6-dihydropyridine-1(2H)-carboxylate(C21)

A reaction vessel containing a suspension of C20 (6.11 g, 13.6 mmol),tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate(5.04 g, 16.3 mmol), aqueous sodium carbonate solution (1 M; 40.8 mL,40.8 mmol), and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (497 mg,0.679 mmol) in 1,4-dioxane (100 mL) was evacuated and charged withnitrogen. This evacuation cycle was repeated twice, and then thereaction mixture was stirred at 85° C. for 16 hours, whereupon thereaction mixture was diluted with water (40 mL) and extracted with ethylacetate (3×150 mL). The combined organic layers were dried over sodiumsulfate, filtered, and concentrated in vacuo. Purification via silicagel chromatography (Gradient: 0% to 8% methanol in dichloromethane)provided C21 as a yellow oil. Yield: 5.47 g, 9.91 mmol, 73%. ¹H NMR (600MHz, chloroform-d) δ 7.10 (br d, J=8.2 Hz, 1H), 6.98 (dd, J=7.9, 7.9 Hz,1H), 6.81 (br d, J=7.7 Hz, 1H), 5.79 (br s, 1H), 5.23 (s, 2H), 5.07 (s,2H), 4.03 (br s, 2H), 3.83-3.74 (m, 4H), 3.59 (br s, 2H), 2.52 (br s,2H), 1.49 (s, 9H), 1.01-0.89 (m, 4H), 0.01 (s, 9H), 0.01 (s, 9H).

Step 3. Synthesis of tert-butyl4-(2,3-bis{[2-(trimethylsilyl)ethoxy]methoxy}phenyl)piperidine-1-carboxylate(C22)

A solution of C21 (12.5 g, 22.6 mmol) in methanol (300 mL) was treatedwith 10% palladium on carbon (2.94 g, 2.76 mmol) and hydrogenated for 16hours at 40 psi and 25° C. LCMS analysis at this point indicatedconversion to the product: LCMS m/z 576.0 [M+Na⁺]. After the reactionmixture had been filtered, and the filter cake had been washed withmethanol (2×100 mL), the combined filtrates were concentrated in vacuoto afford C22 as a colorless oil. Yield: 11.2 g, 20.1 mmol, 89%. ¹H NMR(400 MHz, chloroform-d) δ 7.05-6.97 (m, 2H), 6.83 (dd, J=6.9, 2.5 Hz,1H), 5.22 (s, 2H), 5.13 (s, 2H), 4.38-4.10 (br m, 2H), 3.90-3.82 (m,2H), 3.81-3.73 (m, 2H), 3.22 (tt, J=12.2, 3.5 Hz, 1H), 2.79 (br dd,J=12.8, 12.8 Hz, 2H), 1.78 (br d, J=13 Hz, 2H), 1.65-1.52 (m, 2H), 1.48(s, 9H), 1.04-0.91 (m, 4H), 0.03 (s, 9H), 0.00 (s, 9H).

Step 4. Synthesis of4-(2,3-bis{[2-(trimethylsilyl)ethoxy]methoxy}phenyl)piperidine (C23)

To a room temperature (15° C.) solution of C22 (7.23 g, 13.0 mmol) indichloromethane (90 mL) was added 2,6-dimethylpyridine (2.39 g, 22.3mmol), followed by drop-wise addition of trimethylsilyltrifluoromethanesulfonate (3.80 g, 17.1 mmol). The reaction mixture wasstirred at 15° C. for 16 hours, whereupon additional2,6-dimethylpyridine (909 mg, 8.48 mmol) and trimethylsilyltrifluoromethanesulfonate (1.45 g, 6.52 mmol) were added. After stirringat room temperature (15° C.) for another 5 hours, LCMS analysis of thereaction mixture indicated the presence of product: LCMS m/z 454.1[M+H]⁺. The reaction mixture was concentrated in vacuo, and the residuewas washed sequentially with aqueous ammonium chloride solution (3×100mL) and saturated aqueous sodium chloride solution (100 mL), dried oversodium sulfate, filtered, and concentrated under reduced pressure toafford C23 as a brown oil (6.6 g). This material was taken directly tothe following step.

Step 5. Synthesis of methyl2-{[4-(2,3-bis{[2-(trimethylsilyl)ethoxy]methoxy}phenyl)piperidin-1-yl]methyl}-1-(2-methoxyethyl)-1H-benzimidazole-6-carboxylate(C24)

To a solution of C23 (from the previous step; 6.6 g, 513 mmol) inacetonitrile (150 mL) was added P11 (3.08 g, 10.9 mmol), followed bypotassium carbonate (10.1 g, 73.1 mmol), and the reaction mixture wasstirred at room temperature (15° C.) for 16 hours. LCMS analysis at thispoint indicated the presence of the product: LCMS m/z 700.2 [M+H]⁺. Thereaction mixture was filtered, and the filtrate was concentrated invacuo; purification via silica gel chromatography (Gradient: 34% to 56%ethyl acetate in petroleum ether) afforded C24 as a yellow oil. Yield:5.4 g, 7.7 mmol, 59% over 2 steps. ¹H NMR (400 MHz, chloroform-d) δ8.16-8.12 (m, 1H), 7.96 (dd, J=8.5, 1.5 Hz, 1H), 7.73 (d, J=8.5 Hz, 1H),7.04-6.96 (m, 2H), 6.86 (dd, J=6.7, 2.6 Hz, 1H), 5.21 (s, 2H), 5.12 (s,2H), 4.63 (t, J=5.5 Hz, 2H), 3.95 (s, 3H), 3.93-3.83 (m, 4H), 3.80-3.72(m, 4H), 3.31 (s, 3H), 3.17-3.06 (m, 1H), 2.99 (br d, J=11.2 Hz, 2H),2.35-2.22 (m, 2H), 1.81 (br d, half of AB quartet, J=12.6 Hz, 2H),1.75-1.61 (m, 2H), 1.04-0.91 (m, 4H), 0.05 (s, 9H), −0.01 (s, 9H).

Step 6. Synthesis of methyl2-{[4-(2,3-dihydroxyphenyl)piperidin-1-yl]methyl}-1-(2-methoxyethyl)-1H-benzimidazole-6-carboxylate(P14)

A solution of hydrogen chloride in 1,4-dioxane (4 M; 96 mL, 384 mmol)was added to a room temperature (18° C.) solution of C24 (6.40 g, 9.14mmol) in 1,4-dioxane (120 mL). After completion of the addition, thereaction mixture was stirred at room temperature (18° C.) for 16 hours,combined with a similar reaction carried out using C24 (1.00 g, 1.43mmol), and concentrated in vacuo. The residue was treated with a mixtureof dichloromethane and methanol (20:1, 150 mL) and stirred at roomtemperature (18° C.) for 1 hour, whereupon the solid (4.85 g) wascollected via filtration. This material was treated with water (100 mL),and the mixture was adjusted to a pH of 7 to 8 by addition of aqueoussodium bicarbonate solution, stirred at room temperature (18° C.) for 30minutes, and filtered. The filter cake was washed with water (2×20 mL),then mixed with methanol (100 mL) and concentrated in vacuo. Theresulting material was treated with petroleum ether (100 mL) and stirredat room temperature (18° C.) for 30 minutes. After filtration, thefilter cake was mixed with toluene (30 mL) and concentrated in vacuo toprovide P14 as a gray solid. Combined yield: 2.92 g, 6.64 mmol, 63%.LCMS m/z 440.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.21 (d, J=1.6 Hz,1H), 7.81 (dd, J=8.5, 1.6 Hz, 1H), 7.66 (d, J=8.5 Hz, 1H), 6.64-6.51 (m,3H), 4.63 (t, J=5.3 Hz, 2H), 3.88 (s, 3H), 3.84 (s, 2H), 3.75 (t, J=5.3Hz, 2H), 3.22 (s, 3H), 2.97-2.78 (m, 3H), 2.18 (br dd, J=11, 11 Hz, 2H),1.75-1.64 (m, 2H), 1.64-1.49 (m, 2H).

Preparation P15 Methyl2-(chloromethyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylate(P15)

This entire sequence was carried out on large scale. In general, beforereactions, as well as after addition of reagents, reactors wereevacuated to −0.08 to −0.05 MPa and then filled with nitrogen to normalpressure. This process was generally repeated 3 times, and then oxygencontent was assessed to ensure that it was ≤1.0%. For the processes ofextraction and washing of organic layers, mixtures were generallystirred for 15 to 60 minutes and then allowed to settle for 15 to 60minutes before separation of layers.

Step 1. Synthesis of (2S)-2-[(benzyloxy)methyl]oxetane (C25)

This reaction was carried out in three batches of approximately the samescale. A 2000 L glass-lined reactor was charged with 2-methylpropan-2-ol(774.7 kg). Potassium tert-butoxide (157.3 kg, 1402 mol) was added via asolid addition funnel, and the mixture was stirred for 30 minutes.Trimethylsulfoxonium iodide (308.2 kg, 1400 mol) was then added in thesame manner, and the reaction mixture was heated at 55° C. to 65° C. for2 to 3 hours, whereupon (2S)-2-[(benzyloxy)methyl]oxirane (92.1 kg, 561mol) was added at a rate of 5 to 20 kg/hour. After the reaction mixturehad been maintained at 55° C. to 65° C. for 25 hours, it was cooled to25° C. to 35° C., and filtered through diatomaceous earth (18.4 kg). Thefilter cake was rinsed with tert-butyl methyl ether (3×340 kg), and thecombined filtrates were transferred to a 5000 L reactor, treated withpurified water (921 kg), and stirred for 15 to 30 minutes at 15° C. to30° C. The organic layer was then washed twice using a solution ofsodium chloride (230.4 kg) in purified water (920.5 kg), andconcentrated under reduced pressure (≤−0.08 MPa) at ≤45° C. n-Heptane(187 kg) was added, and the resulting mixture was concentrated underreduced pressure (≤−0.08 MPa) at ≤45° C.; the organic phase was purifiedusing silica gel chromatography (280 kg), with sodium chloride (18.5 kg)on top of the column. The crude material was loaded onto the columnusing n-heptane (513 kg), and then eluted with a mixture of n-heptane(688.7 kg) and ethyl acetate (64.4 kg). The three batches were combined,providing C25 as an 85% pure light yellow oil (189.7 kg, 906 mmol, 54%).¹H NMR (400 MHz, chloroform-d), C25 peaks only: δ 7.40-7.32 (m, 4H),7.32-7.27 (m, 1H), 4.98 (dddd, J=8.1, 6.7, 4.9, 3.7 Hz, 1H), 4.72-4.55(m, 4H), 3.67 (dd, component of ABX pattern, J=11.0, 4.9 Hz, 1H), 3.62(dd, component of ABX pattern, J=11.0, 3.7 Hz, 1H), 2.72-2.53 (m, 2H).

Step 2. Synthesis of (2S)-oxetan-2-ylmethanol (C26)

10% Palladium on carbon (30.7 kg) was added through an addition funnelto a 10° C. to 30° C. solution of 85% pure C25 (from previous step;185.3 kg, 884.8 mol) in tetrahydrofuran (1270 kg) in a 3000 L stainlesssteel autoclave reactor. The addition funnel was rinsed with purifiedwater and tetrahydrofuran (143 kg), and the rinses were added to thereaction mixture. After the reactor contents had been purged withnitrogen, they were similarly purged with hydrogen, increasing thepressure to 0.3 to 0.5 MPa and then venting to 0.05 MPa. This hydrogenpurge was repeated 5 times, whereupon the hydrogen pressure wasincreased to 0.3 to 0.4 MPa. The reaction mixture was then heated to 35°C. to 45° C. After 13 hours, during which the hydrogen pressure wasmaintained at 0.3 to 0.5 MPa, the mixture was vented to 0.05 MPa, andpurged five times with nitrogen, via increasing the pressure to 0.15 to0.2 MPa and then venting to 0.05 MPa. After the mixture had been cooledto 10° C. to 25° C., it was filtered, and the reactor was rinsed withtetrahydrofuran (2×321 kg). The filter cake was soaked twice with thisrinsing liquor and then filtered; concentration at reduced pressure(≤−0.06 MPa) was carried out at ≤40° C., affording C26 (62.2 kg, 706mol, 80%) in tetrahydrofuran (251 kg)

Step 3. Synthesis of (2S)-oxetan-2-ylmethyl 4-methylbenzenesulfonate(C27)

4-(Dimethylamino)pyridine (17.5 kg, 143 mol) was added to a 10° C. to25° C. solution of C26 (from the previous step; 62.2 kg, 706 mol) intetrahydrofuran (251 kg) and triethylamine (92.7 kg, 916 mol) indichloromethane (1240 kg). After 30 minutes, p-toluenesulfonyl chloride(174.8 kg, 916.9 mol) was added in portions at intervals of 20 to 40minutes, and the reaction mixture was stirred at 15° C. to 25° C. for 16hours and 20 minutes. Purified water (190 kg) was added; after stirring,the organic layer was washed with aqueous sodium bicarbonate solution(prepared using 53.8 kg of sodium bicarbonate and 622 kg of purifiedwater), and then washed with aqueous ammonium chloride solution(prepared using 230 kg of ammonium chloride and 624 kg of purifiedwater). After a final wash with purified water (311 kg), the organiclayer was filtered through a stainless steel Nutsche filter that hadbeen preloaded with silica gel (60.2 kg). The filter cake was soakedwith dichloromethane (311 kg) for 20 minutes, and then filtered; thecombined filtrates were concentrated at reduced pressure (≤−0.05 MPa)and ≤40° C. until 330 to 400 L remained. Tetrahydrofuran (311 kg) wasthen added, at 15° C. to 30° C., and the mixture was concentrated in thesame manner, to a final volume of 330 to 400 L. The tetrahydrofuranaddition and concentration was repeated, again to a volume of 330 to 400L, affording a light yellow solution of C27 (167.6 kg, 692 mmol, 98%) intetrahydrofuran (251.8 kg). ¹H NMR (400 MHz, chloroform-d), C27 peaksonly: δ 7.81 (d, J=8.4 Hz, 2H), 7.34 (d, J=8.1 Hz, 2H), 4.91 (ddt,J=8.0, 6.7, 3.9 Hz, 1H), 4.62-4.55 (m, 1H), 4.53-4.45 (m, 1H), 4.14 (d,J=3.9 Hz, 2H), 2.75-2.63 (m, 1H), 2.60-2.49 (m, 1H), 2.44 (s, 3H).

Step 4. Synthesis of (2S)-2-(azidomethy)oxetane (C28)

N,N-Dimethylformamide (473 kg), sodium azide (34.7 kg, 534 mol), andpotassium iodide (5.2 kg, 31 mol) were combined in a 3000 L glass-linedreactor at 10° C. to 25° C. After addition of C27 (83.5 kg, 344.6 mol)in tetrahydrofuran (125.4 kg), the reaction mixture was heated to 55° C.to 65° C. for 17 hours and 40 minutes, whereupon it was cooled to 25° C.to 35° C., and nitrogen was bubbled from the bottom valve for 15minutes. tert-Butyl methyl ether (623 kg) and purified water (840 kg)were then added, and the resulting aqueous layer was extracted twicewith tert-butyl methyl ether (312 kg and 294 kg). The combined organiclayers were washed with purified water (2×419 kg) while maintaining thetemperature at 10° C. to 25° C., affording C28 (31.2 kg, 276 mol, 80%)in a solution of the above organic layer (1236.8 kg).

Step 5. Synthesis of 1-[(2S)-oxetan-2-yl]methanamine (C29)

10% Palladium on carbon (3.7 kg) was added through an addition funnel toa 10° C. to 30° C. solution of C28 [from the previous step; 1264 kg(31.1 kg of C28, 275 mol)] in tetrahydrofuran (328 kg) in a 3000 Lstainless steel autoclave reactor. The addition funnel was rinsed withtetrahydrofuran (32 kg), and the rinse was added to the reactionmixture. After the reactor contents had been purged with nitrogen, theywere similarly purged with hydrogen, increasing the pressure to 0.05 to0.15 MPa and then venting to 0.03 to 0.04 MPa. This hydrogen purge wasrepeated 5 times, whereupon the hydrogen pressure was increased to 0.05to 0.07 MPa. The reaction temperature was increased to 25° C. to 33° C.,and the hydrogen pressure was maintained at 0.05 to 0.15 MPa for 22hours, while exchanging the hydrogen every 3 to 5 hours. The mixture wasthen purged five times with nitrogen, via increasing the pressure to0.15 to 0.2 MPa and then venting to 0.05 MPa. After filtration,tetrahydrofuran (92 kg and 93 kg) was used to wash the reactor and thensoak the filter cake. The combined filtrates were concentrated atreduced pressure (≤−0.07 MPa) and ≤45° C., affording C29 (18.0 kg, 207mol, 75%) in tetrahydrofuran (57.8 kg). ¹H NMR (400 MHz, DMSO-d₆), C29peaks only: δ 4.62 (ddt, J=7.6, 6.6, 5.1 Hz, 1H), 4.49 (ddd, J=8.6, 7.3,5.6 Hz, 1H), 4.37 (dt, J=9.1, 5.9 Hz, 1H), 2.69 (d, J=5.1 Hz, 2H),2.55-2.49 (m, 1H), 2.39 (m, 1H).

Step 6. Synthesis of methyl4-nitro-3-{[(2S)-oxetan-2-ylmethyl]amino}benzoate (C30)

Potassium carbonate (58.1 kg, 420 mol) was added to a solution of methyl3-fluoro-4-nitrobenzoate (54.8 kg, 275 mol) in tetrahydrofuran (148 kg)in a 100 L glass-lined reactor, and the mixture was stirred for 10minutes. A solution of C29 (29.3 kg, 336 mol) in tetrahydrofuran (212.9kg) was added, and the reaction mixture was stirred at 20° C. to 30° C.for 12 hours, whereupon ethyl acetate (151 kg) was added, and themixture was filtered through silica gel (29 kg). The filter cake wasrinsed with ethyl acetate (150 kg and 151 kg), and the combinedfiltrates were concentrated at reduced pressure (≤−0.08 MPa) and ≤45° C.to a volume of 222 to 281 L. After the mixture had been cooled to 10° C.to 30° C., n-heptane (189 kg) was added, stirring was carried out for 20minutes, and the mixture was concentrated at reduced pressure (≤−0.08MPa) and ≤45° C. to a volume of 222 L. n-Heptane (181 kg) was againadded into the mixture at a reference rate of 100 to 300 kg/hour, andstirring was continued for 20 minutes. The mixture was sampled untilresidual tetrahydrofuran was ≤5% and residual ethyl acetate was 10% to13%. The mixture was heated to 40° C. to 45° C. and stirred for 1 hour,whereupon it was cooled to 15° C. to 25° C. at a rate of 5° C. to 10° C.per hour, and then stirred at 15° C. to 25° C. for 1 hour. Filtrationusing a stainless steel centrifuge provided a filter cake, which wasrinsed with a mixture of ethyl acetate (5.0 kg) and n-heptane (34 kg),and then stirred with tetrahydrofuran (724 kg) at 10° C. to 30° C. for15 minutes; filtration provided a yellow solid largely composed of C30(57.3 kg, 210 mol, 76%). ¹H NMR (400 MHz, DMSO-d₆) 8.34 (t, J=5.8 Hz,1H), 8.14 (d, J=8.9 Hz, 1H), 7.63 (d, J=1.7 Hz, 1H), 7.13 (dd, J=8.9,1.8 Hz, 1H), 4.99 (dddd, J=7.7, 6.7, 5.3, 4.1 Hz, 1H), 4.55 (ddd, J=8.6,7.3, 5.8 Hz, 1H), 4.43 (dt, J=9.1, 6.0 Hz, 1H), 3.87 (s, 3H), 3.67-3.61(m, 2H), 2.67 (dddd, J=11.1, 8.6, 7.7, 6.2 Hz, 1H), 2.57-2.47 (m, 1H).

Step 7. Synthesis of methyl2-(chloromethyl)-1-[(2)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylate(P15)

A solution of C30 (from the previous step; 51.8 kg, 190 mol) intetrahydrofuran (678 kg), in a 3000 L autoclave reactor, was treatedwith 10% palladium on carbon (5.2 kg) at 10° C. to 30° C. The additionpipe was rinsed with tetrahydrofuran (46 kg) and the rinse was added tothe reaction mixture. After the reactor contents had been purged withnitrogen, they were similarly purged with hydrogen, increasing thepressure to 0.1 to 0.2 MPa and then venting to 0.02 to 0.05 MPa. Thishydrogen purge was repeated 5 times, whereupon the hydrogen pressure wasincreased to 0.1 to 0.25 MPa. The reaction mixture was stirred at 20° C.to 30° C., and every 2 to 3 hours, the mixture was purged with nitrogenthree times, and then purged with hydrogen five times; after each finalhydrogen exchange, the hydrogen pressure was increased to 0.1 to 0.25MPa. After 11.25 hours total reaction time, the reaction mixture wasvented to normal pressure, and purged five times with nitrogen, viaincreasing the pressure to 0.15 to 0.2 MPa and then venting to 0.05 MPa.It was then filtered, and the filter cake was rinsed twice withtetrahydrofuran (64 kg and 63 kg); the combined rinse and filtrate wereconcentrated under reduced pressure (≤−0.08 MPa) and ≤40° C. to a volumeof 128 to 160 L. Tetrahydrofuran (169 kg) was added, and the mixture wasagain concentrated to a volume of 128 to 160 L; this process wasrepeated a total of 4 times, affording a solution of the intermediatemethyl 4-amino-3-{[(2S)-oxetan-2-ylmethyl]amino}benzoate.

Tetrahydrofuran (150 kg) was added to this solution, followed by2-chloro-1,1,1-trimethoxyethane (35.1 kg, 227 mol) and p-toluenesulfonicacid monohydrate (1.8 kg, 9.5 mol). After the reaction mixture had beenstirred for 25 minutes, it was heated at 40° C. to 45° C. for 5 hours,whereupon it was concentrated under reduced pressure to a volume of 135to 181 L. 2-Propanol (142 kg) was added, and the mixture was againconcentrated to a volume of 135 to 181 L, whereupon 2-propanol (36.5 kg)and purified water (90 kg) were added, and stirring was continued untila solution was obtained. This was filtered with an in-line liquidfilter, and then treated with purified water (447 kg) at a referencerate of 150 to 400 kg/hour at 20° C. to 40° C. After the mixture hadbeen cooled to 20° C. to 30° C., it was stirred for 2 hours, and thesolid was collected via filtration with a centrifuge. The filter cakewas rinsed with a solution of 2-propanol (20.5 kg) and purified water(154 kg); after drying, P15 was obtained as a white solid (32.1 kg, 109mol, 57%). ¹H NMR (400 MHz, chloroform-d) δ 8.14-8.11 (m, 1H), 8.01 (dd,J=8.5, 1.1 Hz, 1H), 7.79 (br d, J=8.6 Hz, 1H), 5.26-5.18 (m, 1H), 5.04(s, 2H), 4.66-4.58 (m, 2H), 4.53 (dd, component of ABX pattern, J=15.7,2.7 Hz, 1H), 4.34 (dt, J=9.1, 6.0 Hz, 1H), 3.96 (s, 3H), 2.82-2.71 (m,1H), 2.48-2.37 (m, 1H).

Preparation P16 Methyl2-(chloromethyl)-1-methyl-1H-benzimidazole-6-carboxylate (P16)

Methyl 4-amino-3-(methylamino)benzoate (206 mg, 1.14 mmol) was dissolvedin 1,4-dioxane (11.5 mL) and treated with chloroacetyl chloride (109 μL,1.37 mmol). The mixture was stirred at 100° C. for 3 hours and cooled toroom temperature. Triethylamine (0.8 mL, 7 mmol) and heptane (10 mL)were added and filtered. The filtrate was concentrated under reducedpressure and the crude material was purified by chromatography on silicagel (Eluent: 40% ethyl acetate in heptane) to afford 120 mg of P16(44%). ¹H NMR (400 MHz, chloroform-d) δ 8.14 (s, 1H), 8.01 (d, 1H), 7.78(d, 1H), 4.87 (s, 2H), 3.97 (s, 3H), 3.94 (s, 3H); LCMS m/z 239.1[M+H]⁺.

Preparations P17 and P18 Methyl2-(6-azaspiro[2.5]oct-1-yl)-1-(2-methoxyethyl)-1H-benzimidazole-6-carboxylate,ENT-1 (P17) and Methyl2-(6-azaspiro[2.5]oct-1-yl)-1-(2-methoxyethyl)-1H-benzimidazole-6-carboxylate,ENT-2 (P18)

Step 1. Synthesis of tert-butyl4-(2-ethoxy-2-oxoethylidene)piperidine-1-carboxylate (C31)

A solution of potassium tert-butoxide (65.9 g, 587 mmol) intetrahydrofuran (500 mL) was added to a 0° C. solution of ethyl(diethoxyphosphoryl)acetate (132 g, 589 mmol) in tetrahydrofuran (500mL), and the resulting suspension was stirred at 0° C. for 1 hour,whereupon it was cooled to −50° C. A solution of tert-butyl4-oxopiperidine-1-carboxylate (90.0 g, 452 mmol) in tetrahydrofuran (1.5L) was added drop-wise at −50° C., and the reaction mixture wassubsequently allowed to slowly warm to 20° C., and then to stir for 16hours at 20° C. After addition of water (1 L), the mixture wasconcentrated in vacuo to remove tetrahydrofuran. The aqueous residue wasextracted with ethyl acetate (2×800 mL), and the combined organic layerswere washed with saturated aqueous sodium chloride solution (500 mL),dried over sodium sulfate, filtered, and concentrated under reducedpressure. The resulting material was washed several times with petroleumether (200 mL) to provide C31 as a white solid. Yield: 95.0 g, 353 mmol,78%. ¹H NMR (400 MHz, chloroform-d) δ 5.71 (s, 1H), 4.16 (q, J=7.2 Hz,2H), 3.55-3.43 (m, 4H), 2.94 (br t, J=5.5 Hz, 2H), 2.28 (br t, J=5.5 Hz,2H), 1.47 (s, 9H), 1.28 (t, J=7.0 Hz, 3H).

Step 2. Synthesis of 6-tert-butyl 1-ethyl6-azaspiro[2.5]octane-1,6-dicarboxylate (C32)

To a solution of trimethylsulfoxonium iodide (140 g, 636 mmol) indimethyl sulfoxide (800 mL) was added potassium tert-butoxide (71.2 g,634 mmol) in one portion at 20° C. After the reaction mixture had beenstirred at 20° C. for 1.5 hours, a solution of C31 (95.0 g, 353 mmol) indimethyl sulfoxide (800 mL) was added drop-wise, and stirring wascontinued at 20° C. for 16 hours. Saturated aqueous sodium chloridesolution (2.0 L) was then added; the resulting mixture was neutralizedby addition of ammonium chloride, and extracted with ethyl acetate (3.0L). The combined organic layers were washed sequentially with water(2×1.0 L) and with saturated aqueous sodium chloride solution (2.0 L),dried over sodium sulfate, filtered, and concentrated in vacuo.Purification via silica gel chromatography (Eluent: 10:1 petroleumether/ethyl acetate) afforded C32 as a yellow oil. ¹H NMR analysisindicated that extraneous aliphatic material was present. Yield: 80 g,280 mmol, 79%. ¹H NMR (400 MHz, chloroform-d), C32 peaks only: δ4.19-4.09 (m, 2H), 3.55-3.39 (m, 3H), 3.27 (ddd, J=13.0, 7.0, 4.5 Hz,1H), 1.76-1.64 (m, 2H), 1.56 (dd, J=8.0, 5.5 Hz, 1H, assumed; partiallyobscured by water peak), 1.47 (s, 9H), 1.47-1.37 (m, 2H), 1.27 (t, J=7.0Hz, 3H), 1.17 (dd, J=5.0, 5.0 Hz, 1H), 0.93 (dd, J=8.0, 4.5 Hz, 1H).

Step 3. Synthesis of6-(tert-butoxycarbonyl)-6-azaspiro[2.5]octane-1-carboxylic Acid (C33)

To a mixture of C32 (80 g, 280 mmol) in tetrahydrofuran (500 mL) andwater (500 mL) was added lithium hydroxide monohydrate (37.4 g, 891mmol) in one portion. The reaction mixture was stirred at 25° C. for 16hours, whereupon it was diluted with water (600 mL) and washed withethyl acetate (3×300 mL). The organic layers were discarded, and theaqueous layer was acidified to pH 3 to 4 by addition of 6 M hydrochloricacid. The resulting mixture was extracted with ethyl acetate (3×600 mL),and the combined organic layers were dried over sodium sulfate,filtered, and concentrated in vacuo. Trituration of the residue withpetroleum ether (300 mL) provided C33 as a white solid. Yield: 42.0 g,164 mmol, 59%. LCMS m/z 278.2 [M+Na⁺]. ¹H NMR (400 MHz, DMSO-d₆) δ12.15-12.03 (br s, 1H), 3.43-3.25 (m, 3H, assumed; partially obscured bywater peak), 3.23-3.12 (m, 1H), 1.64-1.50 (m, 2H), 1.52 (dd, J=7.5, 5.5Hz, 1H), 1.39 (s, 9H), 1.39-1.28 (m, 2H), 0.96-0.88 (m, 2H).

Step 4. Synthesis of tert-butyl1-({4-(methoxycarbonyl)-2-[(2-methoxyethyl)amino]phenyl}carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate(C34)

A solution of C33 (570 mg, 2.23 mmol), C16 (500 mg, 2.23 mmol), andO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU; 1.27 g, 3.34 mmol) in N,N-dimethylformamide(10 mL) was stirred at 30° C. for 30 minutes, whereupon triethylamine(902 mg, 8.91 mmol) was added, and stirring was continued at 30° C. for16 hours. The reaction mixture was then poured into water (60 mL) andextracted with ethyl acetate (3×50 mL). The combined organic layers werewashed with saturated aqueous sodium chloride solution (3×50 mL), driedover sodium sulfate, filtered, and concentrated in vacuo. Silica gelchromatography (Eluent: 1:1 petroleum ether/ethyl acetate) afforded C34as a brown oil, which was taken directly into the following step.

Step 5. Synthesis of methyl2-[6-(tert-butoxycarbonyl)-6-azaspiro[2.5]oct-1-yl]-1-(2-methoxyethyl)-1H-benzimidazole-6-carboxylate(C35)

A solution of C34 (from the previous step, 52.23 mmol) in acetic acid(15 mL) was stirred at 50° C. for 16 hours, whereupon it wasconcentrated in vacuo to provide C35 as a brown oil. This material wasused directly in the next step. LCMS m/z 444.1 [M+H]⁺.

Step 6. Synthesis of methyl2-(6-azaspiro[2.5]oct-1-yl)-1-(2-methoxyethyl)-1H-benzimidazole-6-carboxylate(C36)

Trifluoroacetic acid (5 mL) was added to a solution of C35 (from theprevious step; 52.23 mmol) in dichloromethane (10 mL), and the reactionmixture was stirred at 25° C. for 2 hours. After removal of solvents invacuo, the residue was basified via addition of saturated aqueouspotassium carbonate solution (40 mL), and extracted with a mixture ofdichloromethane and methanol (10:1, 3×40 mL). The combined organiclayers were dried over magnesium sulfate, filtered, concentrated invacuo, and subjected to silica gel chromatography (Eluent: 10:1:0.1dichloromethane/methanol/concentrated ammonium hydroxide) to afford C36as a yellow solid. Yield: 640 mg, 1.86 mmol, 83% over three steps. LCMSm/z 344.1 [M+H]⁺.

Step 7. Isolation of methyl2-(6-azaspiro[2.5]oct-1-yl)-1-(2-methoxyethyl)-1H-benzimidazole-6-carboxylate,ENT-1 (P17) and methyl2-(6-azaspiro[2.5]oct-1-yl)-1-(2-methoxyethyl)-1H-benzimidazole-6-carboxylate,ENT-2 (P18)

Separation of C36 (630 mg, 1.83 mmol) into its component enantiomers wascarried out using SFC [Column: Chiral Technologies Chiralpak AD, 10 μm;Mobile phase: 55:45 carbon dioxide/(ethanol containing 0.1% ammoniumhydroxide)]. The first-eluting peak was designated as ENT-1 (P17), andthe second-eluting enantiomer as ENT-2 (P18); both were isolated as paleyellow solids.

P17 Yield: 300 mg, 0.874 mmol, 48%. LCMS m/z 344.1 [M+H]⁺. Retentiontime: 5.10 minutes (Column: Chiral Technologies Chiralpak AD-3, 4.6×150mm, 3 μm; Mobile phase A: carbon dioxide; Mobile phase B: ethanolcontaining 0.05% diethylamine; Gradient: 5% to 40% B over 5.5 minutes,then held at 40% B for 3.0 minutes; Flow rate: 2.5 mL/minute).

P18 Yield: 240 mg, 0.699 mmol, 38%. LCMS m/z 344.1 [M+H]⁺. Retentiontime: 7.35 minutes (Analytical conditions identical to those used forP17).

Preparation P19 Methyl4-amino-3-{[(1-ethyl-1H-imidazol-5-yl)methyl]amino}benzoate (P19)

Step 1. Synthesis of methyl3-{[(1-ethyl-1H-imidazol-5-yl)methyl]amino}-4-nitrobenzoate (C37)

Triethylamine (3.65 mL, 26.2 mmol) was added to a solution of methyl3-fluoro-4-nitrobenzoate (1.00 g, 5.02 mmol) and1-(1-ethyl-1H-imidazol-5-yl)methanamine, dihydrochloride salt (1.00 g,5.05 mmol) in a mixture of tetrahydrofuran (12 mL) and methanol (8 mL).The reaction mixture was stirred at 60° C. for 40 hours, whereupon itwas concentrated in vacuo and purified using silica gel chromatography(Gradient: 0% to 2% methanol in dichloromethane) to afford C37 as anorange solid. Yield: 1.27 g, 4.17 mmol, 83%. ¹H NMR (400 MHz,chloroform-d) δ 8.24 (d, J=8.8 Hz, 1H), 7.98-7.91 (m, 1H), 7.68 (d,J=1.7 Hz, 1H), 7.57 (br s, 1H), 7.33 (dd, J=8.8, 1.7 Hz, 1H), 7.11 (brs, 1H), 4.53 (d, J=4.9 Hz, 2H), 3.99 (q, J=7.3 Hz, 2H), 3.95 (s, 3H),1.47 (t, J=7.3 Hz, 3H).

Step 2. Synthesis of methyl4-amino-3-{[(1-ethyl-1H-imidazol-5-yl)methyl]amino}benzoate (P19)

A mixture of wet palladium on carbon (144 mg) and C37 (412 mg, 1.35mmol) in methanol (13 mL) was stirred under a balloon of hydrogen for 16hours at 25° C. The reaction mixture was then filtered through a pad ofdiatomaceous earth and the filtrate was concentrated in vacuo to affordP19 as a gray solid. Yield: 340 mg, 1.24 mmol, 92%. ¹H NMR (400 MHz,methanol-d₄) δ 7.66 (br s, 1H), 7.38-7.29 (m, 2H), 6.97 (br s, 1H), 6.67(d, J=7.9 Hz, 1H), 4.35 (s, 2H), 4.11 (q, J=7.3 Hz, 2H), 3.81 (s, 3H),1.44 (t, J=7.3 Hz, 3H).

Preparation P20 Methyl 4-amino-3-(methylamino)benzoate (P20)

Step 1. Synthesis of methyl 3-(methylamino)-4-nitrobenzoate (D1)

To a solution of methyl 3-fluoro-4-nitrobenzoate (5.10 g, 25.6 mmol) intetrahydrofuran (60 mL) was added methylamine (38.4 mL, 76.8 mmol, 2 Min tetrahydrofuran), drop-wise, over 10 minutes. The pale yellowsolution turned deep orange immediately upon addition and was stirredfor 2 hours at room temperature. The reaction mixture was then dilutedwith diethyl ether (100 mL) and the organic layer was washedsequentially with water (50 mL) and saturated aqueous sodium chloridesolution (50 mL). The organic layer was dried over sodium sulfate,filtered, and concentrated under reduced pressure to yield 5.26 g ofmethyl 3-(methylamino)-4-nitrobenzoate (98%) as a deep orange solid.LCMS m/z 211.1 [M+H]⁺. ¹H NMR (400 MHz, chloroform-d) δ 8.22 (d, J=8.9Hz, 1H), 8.00 (br s, 1H), 7.56 (d, J=1.7 Hz, 1H), 7.25 (dd, J=8.9, 1.7Hz, 1H, assumed; partially obscured by solvent peak), 3.95 (s, 3H), 3.09(d, J=5.1 Hz, 3H).

Step 2. Synthesis of methyl 4-amino-3-(methylamino)benzoate (P20)

A solution of D1 (5.26 g, 25.0 mmol) in ethanol (150 mL) was added to a500 mL Parr® bottle previously charged with 10% palladium on carbon (50%water; 1 g). The mixture was shaken under 50 psi hydrogen atmosphere for1 hour at room temperature, whereupon it was filtered and the filtercake was rinsed with ethanol (100 mL). The filtrate was concentratedunder reduced pressure to yield 4.38 g of P20 (97%) as an off-whitesolid. LCMS m/z 181.1 [M+H]⁺. ¹H NMR (400 MHz, chloroform-d) δ 7.46 (dd,J=8.0, 1.9 Hz, 1H), 7.34 (d, J=1.8 Hz, 1H), 6.68 (d, J=8.0 Hz, 1H), 3.87(s, 3H), 3.72 (br s, 2H), 3.21 (br s, 1H), 2.91 (s, 3H).

Preparations P21 and P22 5-Bromo-N³-methylpyridine-2,3-diamine (P21) and5-Bromo-N³,6-dimethylpyridine-2,3-diamine (P22)

Intermediate P21 was synthesized according to the literature procedure(Choi, J. Y. et al. J. Med. Chem. 2012, 55, 852-870). Intermediate P22was synthesized using the same method.

Preparation P23 Methyl2-(chloromethyl)-1-[(1-methyl-1H-imidazol-5-yl)methyl]-1H-benzimidazole-6-carboxylate(P23)

Step 1. Synthesis of methyl3-{[(1-methyl-1H-imidazol-5-yl)methyl]amino}-4-nitrobenzoate (D2)

To a colorless solution of methyl 3-fluoro-4-nitrobenzoate (1.0 g, 5.0mmol) in N,N-dimethylformamide (10 mL) was slowly added1-(1-methyl-1H-imidazol-5-yl)methanamine (670 mg, 6.0 mmol) andtriethylamine (762 mg, 7.53 mmol). The reaction mixture was stirred at60° C. for 16 hours, whereupon it was poured into water (30 mL) andextracted with dichloromethane (3×30 mL). The combined organic layerswere dried over sodium sulfate, filtered, and concentrated under reducedpressure. The crude material was purified by silica gel chromatography(Eluent: 20% methanol in dichloromethane). The obtained yellow solid wastriturated with 30:1 petroleum ether/ethyl acetate to deliver D2 (1.2 g,82%) as a yellow solid. LCMS m/z 290.9 [M+H]⁺. ¹H NMR (400 MHz,chloroform-d) δ 8.25 (d, J=8.9 Hz, 1H), 7.98-7.92 (m, 1H), 7.70 (d,J=1.7 Hz, 1H), 7.49 (s, 1H), 7.34 (dd, J=8.9, 1.7 Hz, 1H), 7.12 (s, 1H),4.54 (d, J=5.0 Hz, 2H), 3.96 (s, 3H), 3.67 (s, 3H).

Step 2. Synthesis of methyl4-amino-3-{[(1-methyl-1H-imidazol-5-yl)methyl]amino}benzoate (D3)

To a suspension of D2 (5.46 g, 18.8 mmol) in methanol (160 mL) was addedwet 10% palladium on carbon (1 g). The mixture was stirred under 1atmosphere of hydrogen for 36 hours at 20° C. The reaction mixture wasfiltered and the filter cake was rinsed with methanol (200 mL). Thefiltrate was concentrated under reduced pressure to deliver D3 (4.8 g,98%) as a brown solid. LCMS m/z 260.9 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆)δ 7.56 (s, 1H), 7.18 (br d, J=8.1 Hz, 1H), 7.12 (br s, 1H), 6.87 (s,1H), 6.55 (d, J=8.2 Hz, 1H), 5.50 (s, 2H), 4.84 (t, J=5.2 Hz, 1H), 4.23(d, J=5.0 Hz, 2H), 3.73 (s, 3H), 3.63 (s, 3H).

Step 3. Synthesis of methyl2-(hydroxymethyl)-1-[(1-methyl-1H-imidazol-5-yl)methyl]-1H-benzimidazole-6-carboxylate(D4)

A mixture of D3 (780 mg, 3.00 mmol) and 2-hydroxyacetic acid (342 mg,4.49 mmol) in 1,3,5-trimethylbenzene (8 mL) was stirred at 140° C. for14 hours and at 25° C. for 48 hours. The clear yellow solution wasdecanted off to give a brown residue that was dissolved in methanol (50mL) and concentrated under reduced pressure. The crude material waspurified by silica gel chromatography (Eluent: 20% methanol indichloromethane) to provide D4 (318 mg, 35%) as a yellow foam. LCMS m/z300.9 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.13-8.11 (m, 1H), 7.83 (dd,J=8.4, 1.6 Hz, 1H), 7.71 (d, J=8.5 Hz, 1H), 7.59 (s, 1H), 6.58 (s, 1H),5.69 (s, 2H), 4.75 (s, 2H), 3.84 (s, 3H), 3.53 (s, 3H).

Step 4. Synthesis of methyl2-(chloromethyl)-1-[(1-methyl-1H-imidazol-5-yl)methyl]-1H-benzimidazole-6-carboxylate(P23)

To a suspension of D4 (500 mg, 1.66 mmol) in dichloromethane (10 mL) andN,N-dimethylformamide (3 mL) was added thionyl chloride (990 mg, 0.60mL, 8.32 mmol), drop-wise, at room temperature. The reaction mixture wasstirred at room temperature for 1 hour, then concentrated under reducedpressure. The resultant brown residue was triturated withdichloromethane (10 mL). The solids were collected by filtration andrinsed with dichloromethane (5 mL) to provide P23 (431 mg, 73%) as anoff-white solid. LCMS m/z 318.9+[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 9.17(s, 1H), 8.31 (s, 1H), 7.93 (br d, J=8.5 Hz, 1H), 7.82 (d, J=8.5 Hz,1H), 7.11 (s, 1H), 5.92 (s, 2H), 5.13 (s, 2H), 3.87 (s, 3H), 3.87 (s,3H).

Preparation P245-Chloro-2-(chloromethyl)-3-methyl-3H-imidazo[4,5-b]pyridine (P24)

Step 1. Synthesis of 6-chloro-N-methyl-3-nitropyridin-2-amine (D5)

To a suspension of 2,6-dichloro-3-nitropyridine (200 g, 1.04 mol) andNa₂CO₃ (132 g, 1.24 mol) in ethanol (1 L) was added a solution ofmethylamine in tetrahydrofuran (2.0 M; 622 mL, 1.24 mol), drop-wise, at0° C. via syringe. After completion of the addition, the reactionmixture was stirred at 18° C. for 6 hours. The mixture was filtered andthe filtrate was concentrated under reduced pressure to give a yellowsolid. The crude material was purified by silica gel chromatography(Gradient: 0% to 5% ethyl acetate in petroleum ether) to afford D5 (158g, 81% yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.72 (br s,1H), 8.41 (d, J=8.6 Hz, 1H), 6.76 (d, J=8.6 Hz, 1H), 3.00 (d, J=4.8 Hz,3H).

Step 2. Synthesis of 6-chloro-N²-methylpyridine-2,3-diamine (D6)

To a mixture of D5 (15.8 g, 84.2 mmol) in acetic acid (100 mL) was addediron powder (15.4 g, 276 mmol). The reaction mixture was stirred at 80°C. for 3 hours, whereupon it was cooled to room temperature andfiltered. The filter cake was washed with ethyl acetate (2×100). Thecombined organic layers were concentrated under reduced pressure and thecrude material was purified by silica gel chromatography (Eluent: 1:1ethyl acetate/petroleum ether) to afford D6 (8.40 g, 63% yield) as abrown solid. ¹H NMR (400 MHz, chloroform-d) δ 6.79 (d, J=7.7 Hz, 1H),6.49 (d, J=7.7 Hz, 1H), 3.00 (s, 3H).

Step 3. Synthesis of5-chloro-2-(chloromethyl)-3-methyl-3H-imidazo[4,5-b]pyridine (P24)

To a solution of D6 (50.0 g, 317 mmol) in 1,4-dioxane (1.2 L) was addedchloroacetyl chloride (55.5 mL, 698 mmol) and the reaction mixture wasstirred at 15° C. for 50 minutes. It was then concentrated under reducedpressure to give a brown solid, which was taken up in trifluoroaceticacid (1.2 L) and stirred at 80° C. for 60 hours. The mixture wasconcentrated under reduced pressure to give a brown oil, which wasdiluted with ethyl acetate (1 L) and neutralized by addition ofsaturated aqueous sodium bicarbonate solution. When carbon dioxideevolution subsided, the layers were separated, and the aqueous layer wasextracted with ethyl acetate (200 mL). The organic extracts werecombined, dried over sodium sulfate, filtered, and concentrated underreduced pressure. The crude material was purified by silica gelchromatography (Gradient: 10% to 25% ethyl acetate in petroleum ether)to afford P24 (61.0 g, 79% yield) as a yellow solid. LCMS m/z 215.7(dichloro isotope pattern observed) [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ8.13 (d, J=8.3 Hz, 1H), 7.37 (d, J=8.4 Hz, 1H), 5.11 (s, 2H), 3.84 (s,3H).

Examples 1 and 22-({4-[2-(4-Chloro-2-fluorophenyl)-1,3-benzodioxol-4-yl]piperazin-1-yl}methyl)-1-(2-methoxyethyl)-1H-benzimidazole-6-carboxylicacid, ENT-X1, trifluoroacetate Salt (1) [from C39]; and2-({4-[2-(4-Chloro-2-fluorophenyl)-1,3-benzodioxol-4-yl]piperazin-1-yl}methyl)-1-(2-methoxyethyl)-1H-benzimidazole-6-carboxylicacid, ENT-X2, trifluoroacetate salt (2) [from C40]

Step 1. Synthesis of methyl2-({4-[2-(4-chloro-2-fluorophenyl)-1,3-benzodioxol-4-yl]piperazin-1-yl}methyl)-1-(2-methoxyethyl)-1H-benzimidazole-6-carboxylate(C38)

This experiment was carried out in two batches of identical scale. Areaction vessel containing a mixture of C2 (500 mg, 1.52 mmol), P12 (530mg, 1.59 mmol),[2′,6′-bis(propan-2-yloxy)biphenyl-2-yl](dicyclohexyl)phosphane (Ruphos;142 mg, 0.304 mmol), tris(dibenzylideneacetone)dipalladium(0) (139 mg,0.152 mmol), and cesium carbonate (1.48 g, 4.54 mmol) in toluene (15 mL)was evacuated and charged with nitrogen. This evacuation cycle wasrepeated twice, whereupon the reaction mixture was stirred at 100° C.for 16 hours, combined with the second batch, and filtered. The filtratewas concentrated, and the residue was subjected to silica gelchromatography (Gradient: 0% to 60% ethyl acetate in petroleum ether)followed by preparative thin-layer chromatography (Eluent: 1:1 petroleumether/ethyl acetate) to afford C38 as a pale yellow solid. Combinedyield: 600 mg, 1.03 mmol, 34%. LCMS m/z 581.0♦ [M+H]⁺.

Step 2. Isolation of methyl2-({4-[2-(4-chloro-2-fluorophenyl)-1,3-benzodioxol-4-yl]piperazin-1-yl}methyl)-1-(2-methoxyethyl)-1H-benzimidazole-6-carboxylate,ENT-1 (C39) and methyl2-({4-[2-(4-chloro-2-fluorophenyl)-1,3-benzodioxol-4-yl]piperazin-1-yl}methyl)-1-(2-methoxyethyl)-1H-benzimidazole-6-carboxylate,ENT-2 (C40)

Separation of C38 (780 mg, 1.34 mmol) into its component enantiomers waseffected using SFC [Column: Chiral Technologies Chiralpak AD, 10 μm;Mobile phase: 3:2 carbon dioxide/(ethanol containing 0.1% ammoniumhydroxide)]. The first-eluting enantiomer, designated as ENT-1 (C39),was obtained as a white solid. Yield: 282 mg, 0.485 mmol, 36%. LCMS m/z581.0♦ [M+H]⁺. Retention time 1.90 minutes (Column: Chiral TechnologiesChiralpak AD-3, 4.6×50 mm, 3 μm; Mobile phase A: carbon dioxide; Mobilephase B: ethanol containing 0.05% diethylamine; Gradient: 5% B for 0.20minutes, then 5% to 40% B over 1.4 minutes, then held at 40% B for 1.05minutes; Flow rate: 4.0 mL/minute).

The second-eluting enantiomer, designated as ENT-2, (C40), was subjectedto a second purification using SFC [Column: Chiral TechnologiesChiralpak AD, 10 μm; Mobile phase: 3:2 carbon dioxide/(ethanolcontaining 0.1% ammonium hydroxide)]. This provided C40 as a pale brownsolid. Yield: 280 mg, 0.482 mmol, 36%. LCMS m/z 581.0♦ [M+H]⁺. Retentiontime 2.18 minutes (Analytical conditions identical to those used forC39).

Step 3. Synthesis of2-({4-[2-(4-chloro-2-fluorophenyl)-1,3-benzodioxol-4-yl]piperazin-1-yl}methyl)-1-(2-methoxyethyl)-1H-benzimidazole-6-carboxylicAcid, ENT-X1, trifluoroacetate Salt (1) [from C39]

Aqueous lithium hydroxide solution (2 M; 0.30 mL, 0.60 mmol) was addedto a solution of C39 (70 mg, 0.12 mmol) in a mixture of methanol (3 mL)and tetrahydrofuran (3 mL). After the reaction mixture had been stirredat 25° C. for 16 hours, aqueous lithium hydroxide solution (2 M; 0.30mL, 0.60 mmol) was again added, and stirring was continued for anadditional 20 hours. The reaction mixture was then adjusted to pH 7 viaaddition of 1 M hydrochloric acid, and subsequently concentrated invacuo to remove methanol and tetrahydrofuran. The residue was adjustedto a pH of 5 to 6 by addition of trifluoroacetic acid and then purifiedvia reversed-phase HPLC (Column: Agela Durashell C18, 5 μm; Mobile phaseA: 0.1% trifluoroacetic acid in water; Mobile phase B: acetonitrile;Gradient: 30% to 60% B) to afford 1 as a white solid. Yield: 40.5 mg,59.5 μmol, 50%. LCMS m/z 567.0♦ [M+H]⁺. ¹H NMR (400 MHz, methanol-d₄) δ8.37 (br s, 1H), 8.07 (dd, J=8.5, 1.5 Hz, 1H), 7.79 (d, J=8.6 Hz, 1H),7.59 (dd, J=8.0, 8.0 Hz, 1H), 7.34 (dd, J=10.2, 2.0 Hz, 1H), 7.30 (brdd, J=8.3, 2.0 Hz, 1H), 7.22 (s, 1H), 6.87 (dd, J=8.1, 8.1 Hz, 1H), 6.63(br d, J=8 Hz, 1H), 6.60 (br d, J=8 Hz, 1H), 4.70 (s, 2H), 4.65 (t,J=4.8 Hz, 2H), 3.75 (t, J=4.8 Hz, 2H), 3.59-3.42 (m, 8H), 3.29 (s, 3H).

Step 4. Synthesis of2-({4-[2-(4-chloro-2-fluorophenyl)-1,3-benzodioxol-4-yl]piperazin-1-yl}methyl)-1-(2-methoxyethyl)-1H-benzimidazole-6-carboxylicAcid, ENT-X2, trifluoroacetate Salt (2) [from C40]

Aqueous lithium hydroxide solution (2 M; 0.30 mL, 0.60 mmol) was addedto a solution of C40 (69 mg, 0.12 mmol) in a mixture of methanol (3 mL)and tetrahydrofuran (3 mL). After the reaction mixture had been stirredat 25° C. for 16 hours, aqueous lithium hydroxide solution (2 M; 0.30mL, 0.60 mmol) was again added, and stirring was continued for anadditional 20 hours. The reaction mixture was adjusted to pH 7 viaaddition of 1 M hydrochloric acid, and then concentrated in vacuo toremove methanol and tetrahydrofuran. The residue was adjusted to a pH of5 to 6 by addition of trifluoroacetic acid and subsequently purified viareversed-phase HPLC (Column: Agela Durashell C18, 5 μm; Mobile phase A:0.1% trifluoroacetic acid in water; Mobile phase B: acetonitrile;Gradient: 30% to 60% B) to afford 2 as a white solid. Yield: 22.9 mg,33.6 μmol, 28%. LCMS m/z 567.0♦ [M+H]⁺. ¹H NMR (400 MHz, methanol-d₄) δ8.40-8.35 (m, 1H), 8.07 (dd, J=8.6, 1.5 Hz, 1H), 7.79 (d, J=8.6 Hz, 1H),7.59 (dd, J=8.0, 8.0 Hz, 1H), 7.35 (dd, J=10.2, 2.0 Hz, 1H), 7.31 (brdd, J=8, 2 Hz, 1H), 7.22 (s, 1H), 6.87 (dd, J=8.3, 8.0 Hz, 1H), 6.63 (brd, J=8 Hz, 1H), 6.60 (br d, J=8 Hz, 1H), 4.68 (s, 2H), 4.65 (t, J=4.9Hz, 2H), 3.76 (t, J=4.8 Hz, 2H), 3.57-3.40 (m, 8H), 3.29 (s, 3H).

Example 32-({4-[2-(4-Chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-(2-methoxyethyl)-1H-imidazo[4,5-b]pyridine-6-carboxylicacid, trifluoroacetate Salt (3)

Step 1. Synthesis of4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidine(C13, Free Base)

To a solution of P2 (300 mg, 0.670 mmol) in ethyl acetate (3.5 mL) wasadded p-toluenesulfonic acid monohydrate (318 mg, 1.67 mmol). Thereaction mixture was stirred at 60° C. for 1 hour, whereupon it wasbasified by addition of saturated aqueous potassium carbonate solution(20 mL) and extracted with a mixture of dichloromethane and methanol(10:1, 3×50 mL). The combined organic layers were dried over magnesiumsulfate, filtered, and concentrated in vacuo to provide C13, free base,as a brown solid. Yield: 230 mg, 0.661 mmol, 99%.

Step 2. Synthesis of6-bromo-2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-(2-methoxyethyl)-1H-imidazo[4,5-b]pyridine(C41)

A suspension of C13, free base (130 mg, 0.374 mmol), P13 (130 mg, 0.427mmol), and potassium carbonate (172 mg, 1.24 mmol) in acetonitrile (2mL) was stirred at 50° C. for 16 hours. The reaction mixture was thenpurified using preparative thin-layer chromatography (Eluent: ethylacetate) to afford C41 as a brown oil. Yield: 114 mg, 0.185 mmol, 49%.LCMS m/z 617.1 (bromine-chlorine isotope pattern observed) [M+H]⁺.

Step 3. Synthesis of methyl2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-(2-methoxyethyl)-1H-imidazo[4,5-b]pyridine-6-carboxylate(C42)

A solution of C41 (114 mg, 0.185 mmol),1,3-bis(diphenylphosphino)propane (15.3 mg, 37.1 μmol), palladium(II)acetate (8.3 mg, 37 μmol), and triethylamine (187 mg, 1.85 mmol) in amixture of methanol (5 mL) and N,N-dimethylformamide (1 mL) was stirredat 80° C. under carbon monoxide (50 psi) for 16 hours. After thereaction mixture had been diluted with ethyl acetate (50 mL), it waswashed with saturated aqueous sodium chloride solution (2×50 mL), driedover magnesium sulfate, filtered, and concentrated under reducedpressure. Purification using preparative thin-layer chromatography(Eluent: ethyl acetate) provided C42 as a colorless oil. Yield: 60.0 mg,0.101 mmol, 55%. LCMS m/z 617.2 (chlorine isotope pattern observed[M+Na⁺].

Step 4. Synthesis of2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-(2-methoxyethyl)-1H-imidazo[4,5-b]pyridine-6-carboxylicAcid, Trifluoroacetate Salt (3)

To a solution of C42 (60.0 mg, 0.101 mmol) in methanol (2.0 mL) wasadded aqueous sodium hydroxide solution (3 M; 1.0 mL, 3.0 mmol), and thereaction mixture was stirred at 20° C. for 2 hours. It was then adjustedto pH 7 by addition of 1 M hydrochloric acid, and extracted with amixture of dichloromethane and methanol (10:1, 3×30 mL). The combinedorganic layers were dried over magnesium sulfate, filtered, concentratedin vacuo, and purified using reversed-phase HPLC (Column: Boston GreenODS, 5 μm; Mobile phase A: 0.1% trifluoroacetic acid in water; Mobilephase B: acetonitrile; Gradient: 10% to 95% B) to afford 3 as a whitesolid. Yield: 29.6 mg, 42.6 μmol, 42%. LCMS m/z 581.0♦ [M+H]⁺. ¹H NMR(400 MHz, methanol-d₄) δ 9.13 (d, J=1.9 Hz, 1H), 8.74 (d, J=1.9 Hz, 1H),7.63 (dd, J=8.3, 8.3 Hz, 1H), 7.30 (dd, J=10.9, 2.0 Hz, 1H), 7.24 (ddd,J=8.4, 2.0, 0.7 Hz, 1H), 6.89-6.84 (m, 1H), 6.82-6.77 (m, 2H), 4.98-4.89(m, 2H, assumed; largely obscured by water peak), 4.64 (t, J=4.8 Hz,2H), 4.04-3.92 (br m, 2H), 3.75 (dd, J=5.4, 4.2 Hz, 2H), 3.51-3.39 (m,2H), 3.31 (s, 3H), 3.19-3.06 (m, 1H), 2.41-2.24 (m, 2H), 2.24-2.12 (m,2H), 2.06 (d, J=1.0 Hz, 3H).

Examples 4 and 5 Ammonium2-({4-[(2R)-2-(4-chloro-2-fluorophenyl)-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylate(4) and Ammonium2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylate(5)

Step 1. Synthesis of4-[2-(4-chloro-2-fluorophenyl)-1,3-benzodioxol-4-yl]piperidine,Trifluoroacetate Salt (C43)

To a solution of P1 (300 mg, 0.691 mmol) in dichloromethane (5 mL) wasadded trifluoroacetic acid (1.3 mL). The reaction mixture was stirred at29° C. for 2 hours, whereupon it was concentrated in vacuo to afford C43as a brown oil, which was used directly in the following step.

Step 2. Synthesis of methyl2-({4-[(2R)-2-(4-chloro-2-fluorophenyl)-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(28)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylate(C44) and methyl2-({4-[(28)-2-(4-chloro-2-fluorophenyl)-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylate(C45)

To a solution of C43 (from the previous step, 50.691 mmol) inacetonitrile (10 mL) was added P15 (204 mg, 0.692 mmol), followed bypotassium carbonate (956 mg, 6.92 mmol). The reaction mixture wasstirred at 29° C. for 16 hours, whereupon it was filtered; the filtratewas concentrated in vacuo to give a residue, which was purified bypreparative thin-layer chromatography (Eluent: 2:1 petroleum ether/ethylacetate) to provide a mixture of the diastereomeric products as a yellowgum (178 mg). Separation into the two products was carried out via SFC[Column: Chiral Technologies ChiralCel OD, 5 μm; Mobile phase: 55:45carbon dioxide/(methanol containing 0.1% ammonium hydroxide)]. Thefirst-eluting diastereomer, obtained as a yellow oil, was designated asC44. Yield: 44.3 mg, 74.8 μmol, 11% over 2 steps. LCMS m/z 592.1♦[M+H]⁺. Retention time 4.26 minutes (Column: Chiral TechnologiesChiralCel OD-3, 4.6×100 mm, 3 μm; Mobile phase A: carbon dioxide; Mobilephase B: methanol containing 0.05% diethylamine; Gradient: 5% to 40% Bover 4.5 minutes, then held at 40% B for 2.5 minutes; Flow rate: 2.8mL/minute).

The second-eluting diastereomer was subjected to a second purificationvia SFC [Column: Chiral Technologies ChiralCel OD, 5 μm; Mobile phase:3:2 carbon dioxide/(methanol containing 0.1% ammonium hydroxide)],providing the second-eluting diastereomer as a colorless oil, which wasdesignated as C45. Yield: 38 mg, 64 μmol, 9% over 2 steps. LCMS m/z592.1♦ [M+H]⁺. Retention time 4.41 minutes (Analytical conditionsidentical to those used for C44).

The indicated absolute stereochemistries at the dioxolane were assignedvia potency correlation of 5 with a sample of 5, free acid synthesizedfrom intermediate C48; the absolute stereochemistry of that intermediatewas determined via single-crystal X-ray structure determination (seebelow) of C49, a hemisulfate salt of C48.

Step 3. Synthesis of ammonium2-({4-[(2R)-2-(4-chloro-2-fluorophenyl)-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylate(4)

Aqueous lithium hydroxide solution (2 M; 0.80 mL, 1.6 mmol) was added toa solution of C44 (44.3 mg, 74.8 μmol) in a mixture of methanol (1 mL)and tetrahydrofuran (1 mL), and the reaction mixture was stirred at 26°C. for 3 hours. It was then adjusted to pH 7 by addition oftrifluoroacetic acid, and the resulting mixture was concentrated invacuo and purified using reversed-phase HPLC (Column: Agela DurashellC18, 5 μm; Mobile phase A: 0.05% ammonium hydroxide in water; Mobilephase B: acetonitrile; Gradient: 30% to 50% B) to afford 4 as a whitesolid. Yield: 26.6 mg, 44.7 μmol, 60%. LCMS m/z 578.0♦ [M+H]⁺. ¹H NMR(400 MHz, methanol-d₄) δ 8.31 (d, J=1.4 Hz, 1H), 7.96 (dd, J=8.5, 1.6Hz, 1H), 7.66 (d, J=8.5 Hz, 1H), 7.57 (dd, J=8.0, 8.0 Hz, 1H), 7.34 (dd,J=10.1, 2.0 Hz, 1H), 7.29 (br dd, J=8.3, 2.0 Hz, 1H), 7.20 (s, 1H),6.86-6.79 (m, 1H), 6.77 (br dd, component of ABC pattern, J=7.9, 1.3 Hz,1H), 6.73 (dd, component of ABC pattern, J=7.5, 1.4 Hz, 1H), 5.29-5.18(m, 1H), 4.9-4.78 (m, 1H, assumed; partially obscured by water peak),4.68 (dd, J=15.3, 2.7 Hz, 1H), 4.54 (td, J=8.0, 5.9 Hz, 1H), 4.44 (dt,J=9.2, 5.9 Hz, 1H), 4.02 (AB quartet, J_(AB)=13.9 Hz, Δν_(AB)=49.0 Hz,2H), 3.18-3.08 (m, 1H), 3.05-2.96 (m, 1H), 2.81-2.68 (m, 2H), 2.56-2.45(m, 1H), 2.45-2.30 (m, 2H), 2.03-1.88 (m, 2H), 1.88-1.79 (m, 2H).

Step 4. Synthesis of ammonium2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylate(5)

Aqueous lithium hydroxide solution (2 M; 0.80 mL, 1.6 mmol) was added toa solution of C45 (38 mg, 64 μmol) in a mixture of methanol (1 mL) andtetrahydrofuran (1 mL), and the reaction mixture was stirred at 24° C.for 2.5 hours. It was then adjusted to pH 7 by addition of 1 Mhydrochloric acid, and the resulting mixture was concentrated in vacuoand purified using reversed-phase HPLC (Column: Agela Durashell C18, 5μm; Mobile phase A: 0.05% ammonium hydroxide in water; Mobile phase B:acetonitrile; Gradient: 29% to 49% B), providing 5 as a white solid.Yield: 27.9 mg, 46.9 μmol, 73%. LCMS m/z 577.9♦ [M+H]⁺. ¹H NMR (400 MHz,methanol-d₄) δ 8.32 (d, J=1.4 Hz, 1H), 7.96 (dd, J=8.5, 1.5 Hz, 1H),7.66 (d, J=8.5 Hz, 1H), 7.56 (dd, J=8.0, 8.0 Hz, 1H), 7.34 (dd, J=10.2,2.0 Hz, 1H), 7.29 (br dd, J=8.3, 2.0 Hz, 1H), 7.20 (s, 1H), 6.85-6.80(m, 1H), 6.77 (dd, component of ABC pattern, J=8.0, 1.3 Hz, 1H), 6.73(dd, component of ABC pattern, J=7.5, 1.4 Hz, 1H), 5.30-5.20 (m, 1H),4.9-4.79 (m, 1H, assumed; partially obscured by water peak), 4.68 (dd,J=15.4, 2.7 Hz, 1H), 4.62-4.54 (m, 1H), 4.44 (dt, J=9.2, 5.9 Hz, 1H),4.02 (AB quartet, J_(AB)=13.9 Hz, Δν_(AB)=44.6 Hz, 2H), 3.18-3.09 (m,1H), 3.06-2.97 (m, 1H), 2.80-2.67 (m, 2H), 2.55-2.30 (m, 3H), 2.02-1.78(m, 4H).

Alternate Synthesis of Example 5, Free Acid2-({4-[(2S)-2-(4-Chloro-2-fluorophenyl)-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylicacid (5, Free Acid)

Step 1. Isolation of tert-butyl4-[(2R)-2-(4-chloro-2-fluorophenyl)-1,3-benzodioxol-4-yl]piperidine-1-carboxylate(C46) and tert-butyl4-[(2)-2-(4-chloro-2-fluorophenyl)-1,3-benzodioxol-4-yl]piperidine-1-carboxylate(C47)

Separation of P1 (10 g, 23 mmol) into its component enantiomers wascarried out using reversed-phase HPLC [Column: Phenomenex Lux Amylose-1,5 μm; Mobile phase: 9:1 carbon dioxide/(2-propanol containing 0.2%1-aminopropan-2-ol)]. The first-eluting enantiomer was designated asC46, and the second-eluting enantiomer as C47; both were obtained ascolorless oils. The absolute stereochemistries indicated for C46 and C47were assigned based on a single-crystal X-ray structure determinationcarried out on C49, which was synthesized from C47 (see below).

C46 Yield: 4.47 g, 10.3 mmol, 45%. Retention time: 3.98 minutes [Column:Phenomenex Lux Amylose-1, 4.6×250 mm, 5 μm; Mobile phase A: carbondioxide; Mobile phase B: 2-propanol containing 0.2% 1-aminopropan-2-ol;Gradient: 5% B for 1.00 minute, then 5% to 60% B over 8.00 minutes; Flowrate: 3.0 mL/minute; Back pressure: 120 bar].

C47 Yield: 4.49 g, 10.3 mmol, 45%. Retention time: 4.32 minutes(Analytical SFC conditions identical to those used for C46).

Step 2. Synthesis of4-[(2S)-2-(4-chloro-2-fluorophenyl)-1,3-benzodioxol-4-yl]piperidine(C48)

p-Toluenesulfonic acid monohydrate (566 mg, 2.98 mmol) was added to asolution of C47 (1.12 g, 2.58 mmol) in ethyl acetate (26 mL). After thereaction mixture had been heated at 45° C. for 16 hours, it wasconcentrated in vacuo, dissolved in ethyl acetate, and washed withsaturated aqueous sodium bicarbonate solution. The aqueous layers wereextracted with ethyl acetate, and the combined organic layers werewashed with saturated aqueous sodium chloride solution, dried oversodium sulfate, filtered, and concentrated under reduced pressure,affording C48 as a foamy white solid (947 mg), LCMS m/z 334.0♦ [M+H]⁺. Aportion of this material, which still contained some p-toluenesulfonicacid, was used in the synthesis of C50 below.

A second portion of the foamy white solid (440 mg) was dissolved inethyl acetate (25 mL) and washed with saturated aqueous sodiumbicarbonate solution (2×15 mL); the organic layer was dried overmagnesium sulfate, filtered, and concentrated in vacuo to afford C48(350 mg) as a colorless oil that no longer contained p-toluenesulfonicacid. Adjusted yield: 350 mg, 1.05 mmol, 88%. ¹H NMR (400 MHz,chloroform-d) δ 7.53 (dd, J=8.4, 7.8 Hz, 1H), 7.22-7.13 (m, 3H),6.87-6.80 (m, 1H), 6.79-6.71 (m, 2H), 3.23-3.14 (m, 2H), 2.86-2.69 (m,3H), 1.90-1.68 (m, 4H).

Step 3. Synthesis of4-[(2S)-2-(4-chloro-2-fluorophenyl)-1,3-benzodioxol-4-yl]piperidine,hemisulfate salt (C49)

A 0.1 M solution of C48 (the colorless oil from above) in ethyl acetatewas prepared and subjected to a salt screen. Only the sulfate saltformation is described here. A mixture of sulfuric acid (25 μmol) andthe solution of substrate (0.1 M, 250 μL, 25 μmol) was heated to 45° C.for 1 hour, allowed to cool to room temperature, and stirred for 15hours. The resulting suspension was treated with methanol (approximately150 μL) until a solution formed; this was allowed to slowly evaporateovernight, until approximately 50 μL of solvent remained. One of theresulting crystals was analyzed by single-crystal X-ray structuredetermination, establishing the absolute stereochemistry as that shown.

Single-Crystal X-Ray Structural Determination of C49 Single CrystalX-Ray Analysis

Data collection was performed on a Bruker D8 Venture diffractometer atroom temperature. Data collection consisted of omega and phi scans.The structure was solved by intrinsic phasing using SHELX software suitein the triclinic class space group P1. The structure was subsequentlyrefined by the full-matrix least squares method. All non-hydrogen atomswere found and refined using anisotropic displacement parameters.The hydrogen atoms located on nitrogen were found from the Fourierdifference map and refined with distances restrained. The remaininghydrogen atoms were placed in calculated positions and were allowed toride on their carrier atoms. The final refinement included isotropicdisplacement parameters for all hydrogen atoms.The asymmetric unit is comprised of two molecules of protonated C48, onemolecule of doubly deprotonated sulfuric acid, and one molecule fulloccupancy water. Thus, the structure is a hemisulfate salt andhemihydrate. The chlorofluorophenyl ring is disordered and modeled withoccupancy of 60/40, with the ring flipped over two positions.Analysis of the absolute structure using likelihood methods (Hooft,2008) was performed using PLATON (Spek). The results indicate that theabsolute structure has been correctly assigned; the method calculatesthat the probability that the structure is correct is 100.0. The Hooftparameter is reported as 0.061 with an esd of 0.004 and the Parson'sparameter is reported as 0.063 with an esd of 0.005.The final R-index was 3.1%. A final difference Fourier revealed nomissing or misplaced electron density.Pertinent crystal, data collection, and refinement information issummarized in Table E. Atomic coordinates, bond lengths, bond angles,and displacement parameters are listed in Tables F-H.

SOFTWARE AND REFERENCES

-   SHELXTL, Version 5.1, Bruker AXS, 1997-   PLATON, A. L. Spek, J. Appl. Cryst. 2003, 36, 7-13.-   MERCURY, C. F. Macrae, P. R. Edington, P. McCabe, E. Pidcock, G. P.    Shields, R. Taylor, M. Towler, and J. van de Streek, J. Appl. Cryst.    2006, 39, 453-457.-   OLEX2, O. V. Dolomanov, L. J. Bourhis, R. J. Gildea, J. A. K.    Howard, and H. Puschmann, J. Appl. Cryst. 2009, 42, 339-341.-   R. W. W. Hooft, L. H. Straver, and A. L. Spek, J. Appl. Cryst. 2008,    41, 96-103.-   H. D. Flack, Acta Cryst. 1983, A39, 867-881.

TABLE E Crystal data and structure refinement for C49. Empirical formulaC₃₆H₃₈Cl₂F₂N₂O₉S Formula weight 783.64 Temperature 296(2)K Wavelength1.54178 Å Crystal system Triclinic Space group P1 Unit cell dimensions a= 5.9095(2) Å α = 86.5910(10)° b = 6.1712(2) Å β = 89.3680(10)° c =25.6096(8) Å γ = 75.7680(10)° Volume 903.68(5) Å³ Z 1Density(calculated) 1.440 Mg/m³ Absorption coefficient 2.743 mm⁻¹ F(000)408 Crystal size 0.380 × 0.120 × 0.080 mm³ Theta range for datacollection 3.458 to 72.096° Index ranges −7 <= h <= 7, −7 <= k <= 7, −31<=/<= 31 Reflections collected 24619 Independent reflections 6399[R_(int) = 0.0323]] Completeness to theta = 67.679° 96.6% Absorptioncorrection Empirical Refinement method Full-matrix least-squares on F²Data/restraints/parameters 6399/9/495 Goodness-of-fit on F² 1.014 FinalR indices [I > 2σ(I)] R1 = 0.0305, wR2 = 0.0805 R indices(all data) R1 =0.0310, wR2 = 0.0810 Absolute structure parameter 0.058(4) Extinctioncoefficient n/a Largest diff. peak and hole 0.167 and −0.184 e.Å⁻³

TABLE F Atomic coordinates(×10⁴) and equivalent isotropic displacementparameters (Å² × 10³) for C49. U(eq) is defined as one-third of thetrace of the orthogonalized U^(ij) tensor. x y z U(eq) S(1)    8968(1)   2512(1) 4774(1)  33(1) Cl(1)    2534(3)    7001(5) 9863(1) 161(1)F(1)    9192(9)    7761(7) 8721(2)  95(1) C(1)    7533(7)    6719(7)8821(1)  72(1) C(2)    6041(9)    7355(8) 9230(2)  92(1) C(3)    4428(8)   6206(10) 9350(2)  93(2) C(4)    4276(8)    4392(9) 9082(2)  86(1)C(5)    5801(7)    3784(7) 8678(1)  69(1) C(6)    7444(6)    4930(5)8533(1)  56(1) Cl(1′)    2534(3)    7001(5) 9863(1) 161(1) F(1′)   6045(13)    1811(12) 8450(3)  95(1) C(1′)    5801(7)    3784(7)8678(1)  69(1) C(2′)    4276(8)    4392(9) 9082(2)  86(1) C(3′)   4428(8)    6206(10) 9350(2)  93(2) C(4′)    6041(9)    7355(8)9230(2)  92(1) C(5′)    7533(7)    6719(7) 8821(1)  72(1) C(6′)   7444(6)    4930(5) 8533(1)  56(1) Cl(2)  −2047(5)   12265(3)  154(1)157(1) F(2)  −2662(7)    5436(7) 1220(2)  92(1) C(19)  −1591(6)   7059(7) 1154(1)  68(1) C(20)  −2327(8)    8653(9)  752(2)  88(1)C(21)  −1157(9)   10260(8)  665(2)  88(1) C(22)    728(9)   10361(7) 964(2)  80(1) C(23)    1431(6)    8731(6) 1364(1)  65(1) C(24)   274(5)    7058(5) 1472(1)  54(1) Cl(2′)  −2047(5)   12265(3)  154(1)157(1) F(2)    3433(15)    8441(16) 1630(4)  92(1) C(19)    1431(6)   8731(6) 1364(1)  65(1) C(20)    728(9)   10361(7)  964(2)  80(1)C(21)  −1157(9)   10260(8)  665(2)  88(1) C(22)  −2327(8)    8653(9) 752(2)  88(1) C(23)  −1591(6)    7059(7) 1154(1)  68(1) C(24)    274(5)   7058(5) 1472(1)  54(1) N(1)    4370(3)    2950(4) 5713(1)  41(1) N(2)   4133(4)    8236(3) 4386(1)  42(1) O(1)   10923(4)    2331(5) 8233(1) 77(1) O(2)    7874(4)    3730(4) 7651(1)  64(1) O(3)    1766(4)   6201(4) 2352(1)  64(1) O(4)    2966(5)    3591(4) 1729(1)  75(1) O(5)   9024(3)    2305(3) 4214(1)  50(1) O(6)    7650(4)     989(3) 5024(1) 63(1) O(7)   11358(3)    1934(4) 4982(1)  64(1) O(8)    7789(3)   4827(3) 4909(1)  46(1) O(1W)   10276(4)    6879(4) 5537(1)  54(1)C(7)    9086(6)    4293(6) 8090(1)  63(1) C(8)    9234(4)    1745(5)7490(1)  44(1) C(9)   11056(5)     930(6) 7834(1)  54(1) C(10)  12654(5)  −1059(6) 7768(1)  62(1) C(11)   12316(5)  −2213(6) 7338(1) 58(1) C(12)   10459(4)  −1405(5) 6994(1)  47(1) C(13)    8826(4)   623(4) 7066(1)  38(1) C(14)    6762(4)    1637(4) 6711(1)  37(1)C(15)    7243(4)    3516(4) 6343(1)  42(1) C(16)    5126(4)    4639(4)6009(1)  44(1) C(17)    3883(5)    1105(5) 6056(1)  50(1) C(18)   5997(4)   −38(4) 6386(1)  41(1) C(25)    996(6)    5296(6) 1900(1) 60(1) C(26)    3848(5)    4738(4) 2505(1)  45(1) C(27)    4542(6)   3183(5) 2133(1)  52(1) C(28)    6579(6)    1567(5) 2178(1)  56(1)C(29)    7932(6)    1577(5) 2620(1)  56(1) C(30)    7236(5)    3123(5)2992(1)  51(1) C(31)    5126(5)    4786(4) 2944(1)  42(1) C(32)   4261(4)    6474(4) 3352(1)  39(1) C(33)    6145(5)    7543(5) 3544(1) 51(1) C(34)    5139(5)    9272(4) 3932(1)  50(1) C(35)    2313(5)   7116(5) 4227(1)  49(1) C(36)    3263(4)    5420(4) 3826(1)  42(1)

TABLE G Bond lengths [Å] and angles [°] for C49. S(1)—O(5)  1.4463(18)S(1)—O(7)  1.4668(19) S(1)—O(6)  1.475(2) S(1)—O(8)  1.4863(18)Cl(1)—C(3)  1.731(4) F(1)—C(1)  1.314(6) C(1)—C(6)  1.375(5) C(1)—C(2) 1.374(6) C(2)—C(3)  1.343(8) C(2)—H(2)  0.9300 C(3)—C(4)  1.369(8)C(4)—C(5)  1.373(6) C(4)—H(4)  0.9300 C(5)—C(6)  1.370(5) C(5)—H(5) 0.9300 C(6)—C(7)  1.493(5) Cl(1′)—C(3′)  1.731(4) F(1′)—C(1′)  1.357(8)C(1′)—C(6′)  1.370(5) C(1′)—C(2′)  1.373(6) C(2′)—C(3′)  1.369(8)C(2′)—H(2′)  0.9300 C(3′)—C(4′)  1.343(8) C(4′)—C(5′)  1.374(6)C(4′)—H(4′)  0.9300 C(5′)—C(6′)  1.375(5) C(5′)—H(5′)  0.9300 C(6′)—C(7) 1.493(5) Cl(2)—C(21)  1.739(4) F(2)—C(19)  1.312(5) C(19)—C(24) 1.378(5) C(19)—C(20)  1.378(6) C(20)—C(21)  1.348(7) C(20)—H(20) 0.9300 C(21)—C(22)  1.375(7) C(22)—C(23)  1.384(6) C(22)—H(22)  0.9300C(23)—C(24)  1.385(5) C(23)—H(23)  0.9300 C(24)—C(25)  1.485(5)Cl(2′)—C(21′)  1.739(4) F(2′)—C(19′)  1.340(9) C(19′)—C(20′)  1.384(6)C(19′)—C(24′)  1.385(5) C(20′)—C(21′)  1.375(7) C(20′)—H(20′)  0.9300C(21′)—C(22′)  1.348(7) C(22′)—C(23′)  1.378(6) C(22′)—H(22′)  0.9300C(23′)—C(24′)  1.378(5) C(23′)—H(23′)  0.9300 C(24′)—C(25)  1.485(5)N(1)—C(17)  1.480(4) N(1)—C(16)  1.480(3) N(1)—H(1X)  0.95(2) N(1)—H(1Y) 0.97(2) N(2)—C(34)  1.483(4) N(2)—C(35)  1.487(4) N(2)—H(2X)  0.96(2)N(2)—H(2Y)  0.99(2) O(1)—C(9)  1.368(4) O(1)—C(7)  1.445(4) O(2)—C(8) 1.373(3) O(2)—C(7)  1.443(3) O(3)—C(26)  1.380(3) O(3)—C(25)  1.440(3)O(4)—C(27)  1.369(4) O(4)—C(25)  1.447(4) O(1W)—H(1WX)  0.93(2)O(1W)—H(1WY)  0.94(2) C(7)—H(7)  0.9800 C(8)—C(9)  1.374(4) C(8)—C(13) 1.376(4) C(9)—C(10)  1.370(5) C(10)—C(11)  1.387(5) C(10)—H(10)  0.9300C(11)—C(12)  1.390(4) C(11)—H(11)  0.9300 C(12)—C(13)  1.400(4)C(12)—H(12)  0.9300 C(13)—C(14)  1.514(3) C(14)—C(18)  1.518(3)C(14)—C(15)  1.528(3) C(14)—H(14)  0.9800 C(15)—C(16)  1.518(3)C(15)—H(15A)  0.9700 C(15)—H(15B)  0.9700 C(16)—H(16A)  0.9700C(16)—H(16B)  0.9700 C(17)—C(18)  1.513(4) C(17)—H(17A)  0.9700C(17)—H(17B)  0.9700 C(18)—H(18A)  0.9700 C(18)—H(18B)  0.9700C(25)—H(25)  0.9800 C(26)—C(31)  1.367(4) C(26)—C(27)  1.379(3)C(27)—C(28)  1.363(4) C(28)—C(29)  1.394(5) C(28)—H(28)  0.9300C(29)—C(30)  1.376(4) C(29)—H(29)  0.9300 C(30)—C(31)  1.408(4)C(30)—H(30)  0.9300 C(31)—C(32)  1.514(3) C(32)—C(33)  1.527(4)C(32)—C(36)  1.524(3) C(32)—H(32)  0.9800 C(33)—C(34)  1.510(4)C(33)—H(33A)  0.9700 C(33)—H(33B)  0.9700 C(34)—H(34A)  0.9700C(34)—H(34B)  0.9700 C(35)—C(36)  1.515(3) C(35)—H(35A)  0.9700C(35)—H(35B)  0.9700 C(36)—H(36A)  0.9700 C(36)—H(36B)  0.9700O(5)—S(1)—O(7) 109.68(13) O(5)—S(1)—O(6) 109.65(13) O(7)—S(1)—O(6)109.45(15) O(5)—S(1)—O(8) 111.22(11) O(7)—S(1)—O(8) 109.11(11)O(6)—S(1)—O(8) 107.69(11) F(1)—C(1)—C(6) 118.6(4) F(1)—C(1)—C(2)119.1(4) C(6)—C(1)—C(2) 122.1(4) C(3)—C(2)—C(1) 118.9(4) C(3)—C(2)—H(2)120.5 C(1)—C(2)—H(2) 120.5 C(2)—C(3)—C(4) 121.6(4) C(2)—C(3)—Cl(1)119.3(4) C(4)—C(3)—Cl(1) 119.1(5) C(3)—C(4)—C(5) 118.2(5) C(3)—C(4)—H(4)120.9 C(5)—C(4)—H(4) 120.9 C(6)—C(5)—C(4) 122.4(4) C(6)—C(5)—H(5) 118.8C(4)—C(5)—H(5) 118.8 C(5)—C(6)—C(1) 116.7(3) C(5)—C(6)—C(7) 122.7(3)C(1)—C(6)—C(7) 120.6(3) F(1′)—C(1′)—C(6′) 114.7(4) F(1′)—C(1′)—C(2′)122.1(5) C(6′)—C(1′)—C(2′) 122.4(4) C(3′)—C(2′)—C(1′) 118.2(5)C(3′)—C(2v)—H(2′) 120.9 C(1′)—C(2′)—H(2′) 120.9 C(4′)—C(3′)—C(2′)121.6(4) C(4′)—C(3′)—Cl(1′) 119.3(4) C(2′)—C(3′)—Cl(1′) 119.1(5)C(3′)—C(4′)—C(5′) 118.9(4) C(3′)—C(4′)—H(4′) 120.5 C(5′)—C(4′)—H(4′)120.5 C(6′)—C(5′)—C(4′) 122.1(4) C(6′)—C(5′)—H(5′) 118.9C(4′)—C(5′)—H(5′) 118.9 C(1′)—C(6′)—C(5′) 116.7(3) C(1′)—C(6′)—C(7)122.7(3) C(5′)—C(6′)—C(7) 120.6(3) F(2)—C(19)—C(24) 119.3(4)F(2)—C(19)—C(20) 118.1(4) C(24)—C(19)—C(20) 122.5(4) C(21)—C(20)—C(19)118.4(4) C(21)—C(20)—H(20) 120.8 C(19)—C(20)—H(20) 120.8C(20)—C(21)—C(22) 122.4(4) C(20)—C(21)—Cl(2) 118.9(4) C(22)—C(21)—Cl(2)118.7(4) C(21)—C(22)—C(23) 117.8(4) C(21)—C(22)—H(22) 121.1C(23)—C(22)—H(22) 121.1 C(22)—C(23)—C(24) 122.0(4) C(22)—C(23)—H(23)119.0 C(24)—C(23)—H(23) 119.0 C(19)—C(24)—C(23) 116.8(3)C(19)—C(24)—C(25) 120.3(3) C(23)—C(24)—C(25) 122.9(3)F(2′)—C(19′)—C(20′) 123.5(5) F(2′)—C(19′)—C(24′) 113.9(5)C(20′)—C(19′)—C(24′) 122.0(4) C(21′)—C(20′)—C(19′) 117.8(4)C(21′)—C(20′)—H(20′) 121.1 C(19′)—C(20′)—H(20′) 121.1C(22′)—C(21′)—C(20′) 122.4(4) C(22′)—C(21′)—Cl(2′) 118.9(4)C(20′)—C(21′)—Cl(2′) 118.7(4) C(21′)—C(22′)—C(23′) 118.4(4)C(21′)—C(22′)—H(22′) 120.8 C(23′)—C(22′)—H(22′) 120.8C(24′)—C(23′)—C(22′) 122.5(4) C(24′)—C(23′)—H(23′) 118.7C(22′)—C(23′)—H(23′) 118.7 C(23′)—C(24′)—C(19′) 116.8(3)C(23′)—C(24′)—C(25) 120.3(3) C(19′)—C(24′)—C(25) 122.9(3)C(17)—N(1)—C(16) 112.6(2) C(17)—N(1)—H(1X) 110.7(19) C(16)—N(1)—H(1X)108(2) C(17)—N(1)—H(1Y) 108(2) C(16)—N(1)—H(1Y) 112.4(19)H(1X)—N(1)—H(1Y) 105(3) C(34)—N(2)—C(35) 112.2(2) C(34)—N(2)—H(2X)109.7(19) C(35)—N(2)—H(2X) 109.7(19) C(34)—N(2)—H(2Y) 107.7(19)C(35)—N(2)—H(2Y) 110.8(19) H(2X)—N(2)—H(2Y) 107(3) C(9)—O(1)—C(7)106.0(2) C(8)—O(2)—C(7) 105.9(2) C(26)—O(3)—C(25) 105.9(2)C(27)—O(4)—C(25) 105.7(2) H(1WX)—O(1W)—H(1WY) 105(4) O(2)—C(7)—O(1)106.5(3) O(2)—C(7)—C(6) 110.4(3) O(1)—C(7)—C(6) 111.2(3) O(2)—C(7)—C(6′)110.4(3) O(1)—C(7)—C(6′) 111.2(3) O(2)—C(7)—H(7) 109.6 O(1)—C(7)—H(7)109.6 C(6)—C(7)—H(7) 109.6 C(9)—C(8)—O(2) 110.0(2) C(9)—C(8)—C(13)123.4(2) O(2)—C(8)—C(13) 126.6(2) O(1)—C(9)—C(10) 128.1(3)O(1)—C(9)—C(8) 110.1(3) C(10)—C(9)—C(8) 121.7(3) C(9)—C(10)—C(11)116.3(3) C(9)—C(10)—H(10) 121.8 C(11)—C(10)—H(10) 121.8C(10)—C(11)—C(12) 122.0(3) C(10)—C(11)—H(11) 119.0 C(12)—C(11)—H(11)119.0 C(11)—C(12)—C(13) 121.3(3) C(11)—C(12)—H(12) 119.4C(13)—C(12)—H(12) 119.4 C(8)—C(13)—C(12) 115.3(2) C(8)—C(13)—C(14)119.8(2) C(12)—C(13)—C(14) 124.9(2) C(13)—C(14)—C(18) 114.2(2)C(13)—C(14)—C(15) 111.38(19) C(18)—C(14)—C(15) 108.70(19)C(13)—C(14)—H(14) 107.4 C(18)—C(14)—H(14) 107.4 C(15)—C(14)—H(14) 107.4C(16)—C(15)—C(14) 111.7(2) C(16)—C(15)—H(15A) 109.3 C(14)—C(15)—H(15A)109.3 C(16)—C(15)—H(15B) 109.3 C(14)—C(15)—H(15B) 109.3H(15A)—C(15)—H(15B) 107.9 N(1)—C(16)—C(15) 109.9(2) N(1)—C(16)—H(16A)109.7 C(15)—C(16)—H(16A) 109.7 N(1)—C(16)—H(16B) 109.7C(15)—C(16)—H(16B) 109.7 H(16A)—C(16)—H(16B) 108.2 N(1)—C(17)—C(18)110.94(19) N(1)—C(17)—H(17A) 109.5 C(18)—C(17)—H(17A) 109.5N(1)—C(17)—H(17B) 109.5 C(18)—C(17)—H(17B) 109.5 H(17A)—C(17)—H(17B)108.0 C(17)—C(18)—C(14) 110.6(2) C(17)—C(18)—H(18A) 109.5C(14)—C(18)—H(18A) 109.5 C(17)—C(18)—H(18B) 109.5 C(14)—C(18)—H(18B)109.5 H(18A)—C(18)—H(18B) 108.1 O(3)—C(25)—O(4) 106.6(2)O(3)—C(25)—C(24′) 111.0(3) O(4)—C(25)—C(24′) 109.4(3) O(3)—C(25)—C(24)111.0(3) O(4)—C(25)—C(24) 109.4(3) O(3)—C(25)—H(25) 109.9O(4)—C(25)—H(25) 109.9 C(24)—C(25)—H(25) 109.9 C(31)—C(26)—C(27)123.2(3) C(31)—C(26)—O(3) 127.3(2) C(27)—C(26)—O(3) 109.5(2)C(28)—C(27)—O(4) 127.7(2) C(28)—C(27)—C(26) 121.9(3) O(4)—C(27)—C(26)110.3(2) C(27)—C(28)—C(29) 116.3(2) C(27)—C(28)—H(28) 121.9C(29)—C(28)—H(28) 121.9 C(30)—C(29)—C(28) 121.8(3) C(30)—C(29)—H(29)119.1 C(28)—C(29)—H(29) 119.1 C(29)—C(30)—C(31) 121.7(3)C(29)—C(30)—H(30) 119.2 C(31)—C(30)—H(30) 119.2 C(26)—C(31)—C(30)115.1(2) C(26)—C(31)—C(32) 121.5(2) C(30)—C(31)—C(32) 123.4(2)C(31)—C(32)—C(33) 113.3(2) C(31)—C(32)—C(36) 111.48(19)C(33)—C(32)—C(36) 108.02(19) C(31)—C(32)—H(32) 107.9 C(33)—C(32)—H(32)107.9 C(36)—C(32)—H(32) 107.9 C(34)—C(33)—C(32) 110.5(2)C(34)—C(33)—H(33A) 109.6 C(32)—C(33)—H(33A) 109.6 C(34)—C(33)—H(33B)109.6 C(32)—C(33)—H(33B) 109.6 H(33A)—C(33)—H(33B) 108.1N(2)—C(34)—C(33) 110.6(2) N(2)—C(34)—H(34A) 109.5 C(33)—C(34)—H(34A)109.5 N(2)—C(34)—H(34B) 109.5 C(33)—C(34)—H(34B) 109.5H(34A)—C(34)—H(34B) 108.1 N(2)—C(35)—C(36) 110.71(19) N(2)—C(35)—H(35A)109.5 C(36)—C(35)—H(35A) 109.5 N(2)—C(35)—H(35B) 109.5C(36)—C(35)—H(35B) 109.5 H(35A)—C(35)—H(35B) 108.1 C(35)—C(36)—C(32)111.9(2) C(35)—C(36)—H(36A) 109.2 C(32)—C(36)—H(36A) 109.2C(35)—C(36)—H(36B) 109.2 C(32)—C(36)—H(36B) 109.2 H(36A)—C(36)—H(36B)107.9Symmetry transformations used to generate equivalent atoms.

TABLE H Anisotropic displacement parameters (Å² × 10³) for C49. Theanisotropic displacement factor exponent takes the form: −2π²[h²a*²U¹¹ + . . . + 2 h k a* b* U¹²]. U¹¹ U²² U³³ U²³ U¹³ U¹² S(1) 32(1)32(1) 32(1)  −3(1) −2(1) −1(1) Cl(1) 107(1)  258(2)  90(1) −63(1) 19(1)19(1) F(1) 111 (2)  91(2) 98(2) −30(2)  6(2) −46(2)  C(1) 81(2) 71(2)60(2) −20(2) −16(2)  −6(2) C(2) 100(3)  92(3) 74(3) −42(2) −16(2)   7(2)C(3) 70(2) 134(4)  53(2) −27(2) −7(2) 19(3) C(4) 71(2) 116(3)  67(2) 0(2) −1(2) −16(2)  C(5) 75(2) 70(2) 59(2) −11(2) −7(2) −10(2)  C(6)65(2) 54(2) 42(1)  −8(1) −18(1)  −1(1) Cl(1′) 107(1)  258(2)  90(1)−63(1) 19(1) 19(1) F(1′) 111 (2)  91(2) 98(2) −30(2)  6(2) −46(2)  C(1′)75(2) 70(2) 59(2) −11(2) −7(2) −10(2)  C(2′) 71(2) 116(3)  67(2)  0(2)−1(2) −16(2)  C(3′) 70(2) 134(4)  53(2) −27(2) −7(2) 19(3) C(4′) 100(3) 92(3) 74(3) −42(2) −16(2)   7(2) C(5′) 81(2) 71(2) 60(2) −20(2) −16(2) −6(2) C(6′) 65(2) 54(2) 42(1)  −8(1) −18(1)  −1(1) Cl(2) 243(2)  110(1) 80(1)  12(1) −39(1)  26(1) F(2) 88(2) 106(2)  93(2) −12(2) −22(2) −44(2)  C(19) 62(2) 77(2) 62(2) −26(2) −12(2)  −5(2) C(20) 85(3) 98(3)66(2) −20(2) −31(2)  10(2) C(21) 117(3)  74(3) 51(2) −11(2) −10(2) 18(2) C(22) 104(3)  70(2) 60(2)  −9(2)  8(2) −8(2) C(23) 58(2) 73(2)60(2) −13(2) −3(1) −6(2) C(24) 50(2) 60(2) 47(2) −23(1) −4(1) −2(1)Cl(2′) 243(2)  110(1)  80(1)  12(1) −39(1)  26(1) F(2′) 88(2) 106(2) 93(2) −12(2) −22(2)  −44(2)  C(19′) 58(2) 73(2) 60(2) −13(2) −3(1) −6(2)C(20′) 104(3)  70(2) 60(2)  −9(2)  8(2) −8(2) C(21′) 117(3)  74(3) 51(2)−11(2) −10(2)  18(2) C(22′) 85(3) 98(3) 66(2) −20(2) −31(2)  10(2)C(23′) 62(2) 77(2) 62(2) −26(2) −12(2)  −5(2) C(24′) 50(2) 60(2) 47(2)−23(1) −4(1) −2(1) N(1) 30(1) 59(1) 32(1)  −3(1) −4(1) −7(1) N(2) 49(1)38(1) 37(1) −11(1) −5(1)  0(1) O(1) 58(1) 107(2)  55(1) −23(1) −26(1)  6(1) O(2) 64(1) 66(1) 50(1) −21(1) −23(1)  12(1) O(3) 66(1) 62(1) 52(1)−27(1) −19(1)  11(1) O(4) 92(2) 64(1) 56(1) −32(1) −20(1)  10(1) O(5)62(1) 51(1) 34(1)  −5(1) −2(1) −9(1) O(6) 76(1) 43(1) 70(1)  −4(1) 32(1)−14(1)  O(7) 45(1) 68(1) 69(1) −29(1) −22(1)  13(1) O(8) 45(1) 35(1)53(1)  −9(1) −4(1)  2(1) O(1W) 56(1) 50(1) 51(1)  −3(1) −12(1)   1(1)C(7) 68(2) 73(2) 45(2) −12(1) −14(1)  −12(2)  C(8) 38(1) 51(1) 36(1) −4(1) −3(1)  0(1) C(9) 42(1) 76(2) 39(1)  −1(1) −9(1) −4(1) C(10) 38(1)87(2) 48(2)  10(1) −8(1)  6(1) C(11) 45(1) 60(2) 55(2)  9(1)  2(1) 13(1)C(12) 41(1) 46(1) 47(1)  0(1)  3(1)  0(1) C(13) 34(1) 43(1) 34(1)  2(1)−1(1) −4(1) C(14) 30(1) 44(1) 31(1)  −4(1) −1(1)  0(1) C(15) 41(1) 38(1)45(1)  0(1) −12(1)  −7(1) C(16) 44(1) 43(1) 39(1)  −3(1) −6(1)  4(1)C(17) 39(1) 73(2) 42(1)  −1(1) −3(1) −23(1)  C(18) 41(1) 46(1) 39(1) −4(1)  2(1) −14(1)  C(25) 65(2) 62(2) 51(2) −22(1) −9(1) −8(1) C(26)55(1) 37(1) 37(1)  −8(1)  1(1) −2(1) C(27) 72(2) 41(1) 39(1)  −9(1)−2(1) −6(1) C(28) 79(2) 39(1) 43(1) −10(1) 11(1)  1(1) C(29) 62(2) 45(2)48(2)  −2(1)  7(1)  8(1) C(30) 58(2) 45(2) 42(1)  −1(1) −1(1)  1(1)C(31) 54(1) 34(1) 34(1)  −4(1)  2(1) −4(1) C(32) 50(1) 30(1) 33(1) −4(1) −6(1)  0(1) C(33) 63(2) 45(1) 54(2)  −9(1) 17(1) −28(1)  C(34)59(2) 38(1) 58(2)  −9(1) −1(1) −22(1)  C(35) 46(1) 46(1) 56(2) −17(1)16(1) −11(1)  C(36) 39(1) 36(1) 53(1) −15(1) 12(1) −13(1) 

Step 4. Synthesis of methyl2-({4-[(2)-2-(4-chloro-2-fluorophenyl)-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylate(C50)

A solution of C48 (500 mg of the foamy white solid from above, correctedfor p-toluenesulfonic acid: 1.25 mmol) in acetonitrile (6 mL) wastreated with N,N-diisopropylethylamine (0.68 mL, 3.9 mmol) and allowedto stir for 5 minutes at 45° C. After addition of P15 (319 mg, 1.08mmol), stirring at 45° C. was continued for 7.25 hours, whereupon thereaction mixture was diluted with water (6 mL) and acetonitrile (2 mL)at 45° C. The resulting heterogeneous mixture was allowed to cool toroom temperature and stir for 72 hours. More water (5 mL) was added, andafter a further 30 minutes of stirring, the solid was collected viafiltration and washed with a mixture of acetonitrile and water (15:85,3×5 mL), to afford C50 as a white solid with a slight pink cast. Yield:605 mg, 1.02 mmol, 82%. LCMS m/z 592.0♦ [M+H]⁺. ¹H NMR (400 MHz,chloroform-d) δ 8.17 (d, J=1.6 Hz, 1H), 7.96 (dd, J=8.5, 1.5 Hz, 1H),7.73 (d, J=8.4 Hz, 1H), 7.51 (dd, J=8.0, 8.0 Hz, 1H), 7.19 (br s, 1H),7.18-7.14 (m, 2H), 6.85-6.79 (m, 1H), 6.76-6.71 (m, 2H), 5.26-5.18 (m,1H), 4.73 (dd, component of ABX pattern, J=15.3, 5.9 Hz, 1H), 4.67 (dd,component of ABX pattern, J=15.3, 3.5 Hz, 1H), 4.63-4.55 (m, 1H), 4.38(ddd, J=9.1, 6.0, 5.9 Hz, 1H), 3.94 (s, 5H), 3.03-2.89 (m, 2H),2.77-2.65 (m, 2H), 2.51-2.39 (m, 1H), 2.34-2.20 (m, 2H), 1.91-1.76 (m,4H).

Step 5. Synthesis of2-({4-[(2)-2-(4-chloro-2-fluorophenyl)-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylicAcid (5, Free Acid)

A suspension of C50 (595 mg, 1.00 mmol) in methanol (10 mL) was heatedto 45° C. and treated with aqueous sodium hydroxide solution (1 M; 2.01mL, 2.01 mmol). After 21 hours at 45° C., the reaction mixture wasallowed to cool to room temperature; it was then treated with aqueouscitric acid solution (1 M, 1 mL), which brought the pH to 5 to 6. Water(10 mL) was added, and the mixture was stirred for 1 hour, whereupon thesolid was collected by filtration. It was washed with a mixture ofmethanol and water (1:10, 3×5 mL), to afford a solid (433 mg). A portionof this material (300 mg) was stirred with a mixture of heptane andethyl acetate (1:3, 5 mL) at 40° C. for 1 hour; after cooling to roomtemperature with continued stirring, the solid was collected viafiltration, and washed with a mixture of heptane and ethyl acetate (3:1,3×3 mL) to afford 5, free acid, as a white solid. Yield: 260 mg, 0.450mmol, corresponding to 65% for the entire reaction. LCMS m/z 578.0♦[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 12.75 (v br s, 1H), 8.26 (br s, 1H),7.79 (dd, J=8.4, 1.6 Hz, 1H), 7.66-7.56 (m, 3H), 7.40 (dd, J=8.3, 2.0Hz, 1H), 7.35 (s, 1H), 6.87-6.75 (m, 3H), 5.13-5.03 (m, 1H), 4.76 (dd,component of ABX pattern, J=15.3, 7.2 Hz, 1H), 4.62 (dd, component ofABX pattern, J=15.2, 2.8 Hz, 1H), 4.46-4.38 (m, 1H), 4.34 (ddd, J=9.0,5.9, 5.8 Hz, 1H), 3.84 (AB quartet, J_(AB)=13.5 Hz, Δν_(AB)=67.7 Hz,2H), 3.00 (br d, J=11.2 Hz, 1H), 2.84 br (d, J=11.3 Hz, 1H), 2.71-2.56(m, 2H), 2.45-2.34 (m, 1H), 2.28-2.08 (m, 2H), 1.84-1.65 (m, 4H).

This material was determined to be of the same absolute configuration asExample 5 above by comparison of its biological activity with that ofboth 4 and 5: in Assay 2, this sample of 5, free acid exhibited an EC₅₀of 25 nM (geometric mean of 3 replicates). The activity in Assay 2 forthe ammonium salts of Example 4 and Example 5 were >20000 nM (2replicates) and 20 nM (geometric mean of 3 replicates), respectively.

Synthesis of Example 5, 1,3-dihydroxy-2-(hydroxymethyl)propan-2-aminiumSalt 1,3-Dihydroxy-2-(hydroxymethyl)propan-2-aminium2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylate(5,1,3-dihydroxy-2-(hydroxymethyl)propan-2-aminiumSalt)

A mixture of 5, free acid (0.50 g, 0.86 mmol) in tetrahydrofuran (4 mL)was treated with an aqueous solution of2-amino-2-(hydroxymethyl)propane-1,3-diol (Tris, 1.0 M; 0.5 mL, 1.0mmol). After 20 hours, the mixture was concentrated in vacuo withethanol (2×6 mL). The mixture was treated with ethanol (4 mL). Afterstirring for 48 hours, the solid was collected via filtration, washedwith ethanol (2×10 mL) and dried under vacuum to afford 5,1,3-dihydroxy-2-(hydroxymethyl)propan-2-aminium salt, as a white solid.Yield: 410 mg, 0.586 mmol, 68%. ¹H NMR (600 MHz, DMSO-d₆),characteristic peaks: δ 8.19 (s, 1H), 7.78 (br d, J=8.4 Hz, 1H),7.62-7.58 (m, 2H), 7.55 (d, J=8.3 Hz, 1H), 7.40 (dd, J=8.4, 2.0 Hz, 1H),7.35 (s, 1H), 6.85-6.80 (m, 2H), 6.79 (dd, J=6.9, 2.4 Hz, 1H), 5.11-5.05(m, 1H), 4.73 (dd, J=15.2, 7.2 Hz, 1H), 4.60 (dd, J=15.3, 2.9 Hz, 1H),4.45-4.39 (m, 1H), 4.34 (ddd, J=9.0, 6.0, 5.8 Hz, 1H), 3.91 (d, J=13.5Hz, 1H), 3.74 (d, J=13.5 Hz, 1H), 2.99 (br d, J=11.1 Hz, 1H), 2.85 (brd, J=11.3 Hz, 1H), 2.68-2.59 (m, 2H), 2.44-2.37 (m, 1H), 2.25-2.18 (m,1H), 2.17-2.10 (m, 1H), 1.80-1.69 (m, 4H). mp=168° C. to 178° C.

Examples 6 and 7 Ammonium2-({4-[(2R)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylate(6) and Ammonium2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(28)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylate(7)

Step 1. Synthesis of4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidine,p-toluenesulfonate salt (C13)

A solution of P2 (150 mg, 0.335 mmol) and p-toluenesulfonic acidmonohydrate (159 mg, 0.836 mmol) in ethyl acetate (2.0 mL) was stirredat 60° C. for 3.5 hours. The reaction mixture was concentrated in vacuoto afford C13 as a brown oil, which was used directly in the followingstep. LCMS m/z 348.1♦ [M+H]⁺.

Step 2. Synthesis of methyl2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(28)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylate(C51)

To a suspension of C13 (from the previous step; 50.335 mmol) andpotassium carbonate (232 mg, 1.68 mmol) in acetonitrile (5.0 mL) wasadded P15 (99.1 mg, 0.336 mmol). The reaction mixture was stirred at 60°C. for 10 hours, whereupon it was filtered, and the filtrate wasconcentrated in vacuo. After the residue (390 mg) had been combined withthe material from a similar reaction carried out using C13 (50.11 mmol),it was diluted with water (20 mL) and extracted with a mixture ofdichloromethane and methanol (10:1, 3×30 mL). The combined organiclayers were dried over sodium sulfate, filtered, concentrated in vacuo,and subjected to preparative thin-layer chromatography (Eluent: 1:1dichloromethane/methanol), providing C51, a mixture of diastereomers, asa colorless oil. Combined yield: 80.6 mg, 0.133 mmol, 30% over 2 steps.LCMS m/z 606.2♦ [M+H]⁺.

Step 3. Isolation of methyl2-({4-[(2R)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(28)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylate(C52) and methyl2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(28)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylate(C53)

Separation of C51 (180 mg, 0.297 mmol) into its component diastereomerswas carried out via repeated SFC [Column: Chiral Technologies ChiralpakAD, 10 μm; Mobile phase: 65:35 carbon dioxide/(ethanol containing 0.1%ammonium hydroxide)]. The first-eluting diastereomer was designated asC52. Yield: 61.2 mg, 0.101 mmol, 34%. LCMS m/z 627.9♦ [M+Na⁺]. Retentiontime: 5.03 minutes (Column: Chiral Technologies Chiralpak AD-3, 4.6×150mm, 3 μm; Mobile phase A: carbon dioxide; Mobile phase B: ethanolcontaining 0.05% diethylamine; Gradient: 5% to 40% B over 5.5 minutes,then held at 40% B for 3.0 minutes; Flow rate: 2.5 mL/minute).

The second-eluting diastereomer was designated as C53. Upon analysis,this material proved to be contaminated with the corresponding ethylester; it was taken into the hydrolysis step (to generate 7) as thismixture. Yield: 40.0 mg, 66.0 μmol, 22%. LCMS m/z 606.0♦ [M+H]⁺.Retention time: 5.19 minutes (Analytical conditions identical to thoseused for C52).

The indicated absolute stereochemistries at the dioxolane were assignedvia potency correlation of 7 with a sample of 7, free acid synthesizedfrom intermediate P3 (see below, Alternate Synthesis of Example 7, freeacid); the absolute stereochemistry of P3 was established viasingle-crystal X-ray structure determination of C8 (see above).

Step 4. Synthesis of ammonium2-({4-[(2R)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylate(6)

Aqueous lithium hydroxide solution (2 M; 0.990 mL, 1.98 mmol) was addedto a solution of C52 (60 mg, 99 μmol) in a mixture of methanol (1.0 mL)and tetrahydrofuran (1.0 mL), and the reaction mixture was stirred at20° C. for 16 hours. Trifluoroacetic acid was added until the pH of thereaction mixture reached 7, whereupon it was concentrated in vacuo, andthe residue was purified using reversed-phase HPLC (Column: AgelaDurashell C18, 5 μm; Mobile phase A: 0.05% ammonium hydroxide in water;Mobile phase B: acetonitrile; Gradient: 29% to 49% B), affording 6 as awhite solid. Yield: 14.4 mg. 23.6 μmol, 24%. LCMS m/z 592.0♦ [M+H]⁺. ¹HNMR (400 MHz, methanol-d₄), characteristic peaks: δ 8.35 (d, J=1.3 Hz,1H), 7.97 (dd, J=8.5, 1.5 Hz, 1H), 7.67 (d, J=8.5 Hz, 1H), 7.58 (dd,J=8.3, 8.3 Hz, 1H), 7.28 (dd, J=10.9, 2.0 Hz, 1H), 7.21 (br dd, J=8.4,1.9 Hz, 1H), 6.81-6.75 (m, 1H), 6.74-6.68 (m, 2H), 5.33-5.25 (m, 1H),4.72 (dd, J=15.4, 2.7 Hz, 1H), 4.49 (dt, J=9.1, 6.0 Hz, 1H), 4.03 (ABquartet, J_(AB)=13.9 Hz, Δν_(AB)=47.8 Hz, 2H), 3.14 (br d, J=11 Hz, 1H),3.02 (br d, J=11.5 Hz, 1H), 2.88-2.78 (m, 1H), 2.77-2.68 (m, 1H),2.60-2.50 (m, 1H), 2.47-2.32 (m, 2H), 2.03 (d, J=1.1 Hz, 3H), 2.01-1.87(m, 2H), 1.87-1.78 (br m, 2H).

Step 5. Synthesis of ammonium2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylate(7)

Aqueous lithium hydroxide solution (2 M; 0.642 mL, 1.28 mmol) was addedto a solution of C53 (38.9 mg, 64.2 μmol) in a mixture of methanol (1.0mL) and tetrahydrofuran (1.0 mL). After the reaction mixture had beenstirred at 20° C. for 16 hours, it was adjusted to pH 7 by addition oftrifluoroacetic acid, concentrated in vacuo, and purified usingreversed-phase HPLC (Column: Agela Durashell C18, 5 μm; Mobile phase A:0.05% ammonium hydroxide in water; Mobile phase B: acetonitrile;Gradient: 0% to 80% B), affording 7 as a white solid. Yield: 25.1 mg,41.2 μmol, 64%. LCMS m/z 591.9♦ [M+H]⁺. ¹H NMR (400 MHz, methanol-d₄),characteristic peaks: δ 8.34 (d, J=1.5 Hz, 1H), 7.98 (dd, J=8.5, 1.6 Hz,1H), 7.68 (d, J=8.5 Hz, 1H), 7.58 (dd, J=8.3, 8.3 Hz, 1H), 7.28 (dd,J=10.9, 2.0 Hz, 1H), 7.20 (br dd, J=8.4, 1.9 Hz, 1H), 6.81-6.74 (m, 1H),6.74-6.67 (m, 2H), 5.33-5.23 (m, 1H), 4.73 (dd, J=15.4, 2.7 Hz, 1H),4.68-4.61 (m, 1H), 4.48 (dt, J=9.1, 5.9 Hz, 1H), 4.05 (AB quartet,J_(AB)=13.9 Hz, Δν_(AB)=44.1 Hz, 2H), 3.15 (br d, J=11.7 Hz, 1H), 3.03(br d, J=11.6 Hz, 1H), 2.87-2.69 (m, 2H), 2.60-2.49 (m, 1H), 2.48-2.33(m, 2H), 2.03 (br s, 3H), 2.01-1.77 (m, 4H).

Alternate Synthesis of Example 7, Free Acid2-({4-[(2S)-2-(4-Chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylicAcid (7, Free Acid)

Step 1. Synthesis of methyl2-({4-[(2)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylate(C53)

N,N-Diisopropylethylamine (15.1 mL, 86.9 mmol) was added to a mixture ofP3 (8.22 g, 15.8 mmol) in acetonitrile (185 mL); after stirring for 5minutes, P15 (4.57 g, 15.5 mmol) was added, and the reaction mixture washeated at 45° C. After 4 hours, the reaction mixture was concentrated invacuo to half of its original volume, and the resulting mixture wasdiluted with water (100 mL) and extracted with ethyl acetate (2×100 mL).The combined organic layers were washed with water (50 mL), dried overmagnesium sulfate, filtered, and concentrated in vacuo. Silica gelchromatography (Gradient: 50% to 100% ethyl acetate in heptane) affordedC53 as a white solid. Yield: 8.4 g, 13.9 mmol, 88%. LCMS m/z 606.1♦[M+H]⁺. ¹H NMR (600 MHz, DMSO-d₆) δ 8.30 (s, 1H), 7.82 (br d, J=8.4 Hz,1H), 7.67 (d, J=8.4 Hz, 1H), 7.58-7.53 (m, 2H), 7.33 (dd, J=8.4, 2.1 Hz,1H), 6.80-6.76 (m, 2H), 6.76-6.72 (m, 1H), 5.14-5.07 (m, 1H), 4.81 (dd,J=15.2, 7.2 Hz, 1H), 4.67 (dd, J=15.3, 2.8 Hz, 1H), 4.51-4.44 (m, 1H),4.37 (ddd, J=8.9, 5.9, 5.9 Hz, 1H), 3.97 (d, J=13.6 Hz, 1H), 3.87 (s,3H), 3.78 (d, J=13.5 Hz, 1H), 3.02 (br d, J=11.1 Hz, 1H), 2.86 (br d,J=11.3 Hz, 1H), 2.74-2.60 (m, 2H), 2.48-2.41 (m, 1H), 2.29-2.22 (m, 1H),2.21-2.14 (m, 1H), 2.02 (s, 3H), 1.83-1.73 (m, 2H), 1.73-1.64 (m, 2H).

Step 2. Synthesis of2-({4-[(2)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylicAcid (7, Free Acid)

A mixture of C53 (8.40 g, 14.0 mmol) in methanol (135 mL) was heated to45° C., and treated with aqueous sodium hydroxide solution (1 M; 27.7mL, 27.7 mmol). After 20 hours, the reaction mixture was concentrated invacuo to half its original volume. The resulting mixture was dilutedwith water (100 mL), and aqueous citric acid solution (1 M, 15 mL) wasused to adjust the pH to 5 to 6. The resultant solid was filtered,washed with water (2×15 mL), and transferred to a separatory funnel as asolution in ethyl acetate (50 mL); residual water was removed in thisway. The organic layer was dried over magnesium sulfate, filtered,combined with four previously prepared batches from a similar procedure(amount of C53 used in these reactions was 987 mg, 1.63 mmol; 1.15 g,1.90 mmol; 8.57 g, 14.1 mmol; and 12.6 g, 20.8 mmol) and concentrated invacuo. The resulting sticky solid was treated with 10% ethyl acetate inheptane (500 mL). After 4 hours, the solid was collected via filtrationand washed with 10% ethyl acetate in heptane (2×25 mL) to afford 7, freeacid, as a white solid. Yield 29.4 g, 0.527 mmol, 74% for combinedreactions. LCMS 592.2♦ [M+H]⁺. ¹H NMR (600 MHz, DMSO-d₆): δ 12.74 (br s,1H), 8.28 (s, 1H), 7.80 (br d, J=8.4 Hz, 1H), 7.64 (d, J=8.4 Hz, 1H),7.59-7.52 (m, 2H), 7.33 (dd, J=8.4, 2.1 Hz, 1H), 6.81-6.76 (m, 2H),6.76-6.72 (m, 1H), 5.14-5.07 (m, 1H), 4.79 (dd, J=15.3, 7.3 Hz, 1H),4.65 (dd, J=15.2, 2.8 Hz, 1H), 4.51-4.45 (m, 1H), 4.38 (ddd, J=9.0, 5.9,5.9 Hz, 1H), 3.96 (br d, J=13.6 Hz, 1H), 3.78 (br d, J=13.5 Hz, 1H),3.02 (br d, J=11.1 Hz, 1H), 2.86 (br d, J=11.1 Hz, 1H), 2.74-2.60 (m,2H), 2.48-2.41 (m, 1H), 2.29-2.21 (m, 1H), 2.21-2.14 (m, 1H), 2.02 (s,3H), 1.83-1.74 (m, 2H), 1.74-1.64 (m, 2H). This material was determinedto be of the same absolute configuration as Example 7 above bycomparison of its biological activity with that of both 6 and 7: inAssay 2, this sample of 7, free acid exhibited an EC₅₀ of 4.3 nM(geometric mean of 3 replicates). The activity in Assay 2 for theammonium salts of Example 6 and Example 7 were 2400 nM (geometric meanof 5 replicates) and 2.9 nM (geometric mean of 8 replicates),respectively.

Synthesis 7S-1. Synthesis of Example 7,1,3-dihydroxy-2-(hydroxymethyl)propan-2-aminium Salt1,3-Dihydroxy-2-(hydroxymethyl)propan-2-aminium2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylate(7, 1,3-dihydroxy-2-(hydroxymethyl)propan-2-aminium Salt)

A mixture of 7, free acid (2.00 g, 3.38 mmol) in tetrahydrofuran (16 mL)was treated with an aqueous solution of2-amino-2-(hydroxymethyl)propane-1,3-diol (Tris, 1.0 M; 3.55 mL, 3.55mmol). After 18 hours, the reaction mixture was concentrated in vacuoand treated with ethanol (30 mL). After this mixture had been stirredfor 23 hours, the solid was collected via filtration and washed withethyl acetate (2×10 mL) to afford 7,1,3-dihydroxy-2-(hydroxymethyl)propan-2-aminium salt as a white solid.Yield: 1.41 g, 1.98 mmol, 59%. LCMS m/z 592.3♦ [M+H]⁺. ¹H NMR (600 MHz,DMSO-d₆), characteristic peaks: δ 8.20 (s, 1H), 7.79 (d, J=8.4 Hz, 1H),7.59-7.52 (m, 3H), 7.33 (br d, J=8.5 Hz, 1H), 6.81-6.72 (m, 3H),5.14-5.07 (m, 1H), 4.76 (dd, J=15.2, 7.2 Hz, 1H), 4.63 (br d, J=15.4 Hz,1H), 4.50-4.44 (m, 1H), 4.37 (ddd, J=8.9, 5.9, 5.9 Hz, 1H), 3.94 (d,J=13.4 Hz, 1H), 3.76 (d, J=13.4 Hz, 1H), 3.01 (br d, J=11.1 Hz, 1H),2.86 (br d, J=11.2 Hz, 1H), 2.73-2.60 (m, 2H), 2.5-2.41 (m, 1H),2.27-2.20 (m, 1H), 2.20-2.13 (m, 1H), 2.02 (s, 3H), 1.83-1.64 (m, 4H).mp=175° C. to 180° C.

Synthesis 7S-2. Alternative Synthesis of Example 7,1,3-dihydroxy-2-(hydroxymethyl)propan-2-aminium Salt

A 3.3 M solution of 2-smino-2-(hydroxymethyl)-1,3-propanediol (1.0equiv., 1.93 L) in water was added to a solution of 7, free acid (3.74kg) in isopropanol (20 L) at 65° C. Additional isopropanol (19 L) wasadded followed by methanol (19 L) while maintaining the temperature at65° C. The mixture was slowly cooled to 45° C. over 2 hours then heldfor at 45° C. for at least 12 hours. The mixture was then cooled to 5°C. over 3 hours then held at 5° C. for at least 3 hours. The mixture wasthen filtered and the solid was collected washed with ethyl acetate(2×10 mL) to afford 7, 1,3-dihydroxy-2-(hydroxymethyl)propan-2-aminiumsalt as a white solid (yield: 3.64 kg, 80.9%). LCMS and ¹H NMR data wereobtained, which are substantially the same as those in Synthesis 7S-1shown above.

Acquisition of Powder X-Ray Diffraction (PXRD) Data for Form I ofExample 7, 1,3-Dihydroxy-2-(Hydroxymethyl)Propan-2-Aminium Salt

The white solid of the tris salt of Example 7 (from both Synthesis 7S-1and Synthesis 7S-2) was submitted for PXRD analysis and found to be acrystalline material (which is designated as Form I of this anhydrouscrystal form). Powder X-ray diffraction analysis was conducted using aBruker AXS D8 Endeavor diffractometer equipped with a Cu radiationsource. The divergence slit was set at 15 mm continuous illumination.Diffracted radiation was detected by a PSD-Lynx Eye detector, with thedetector PSD opening set at 2.99 degrees. The X-ray tube voltage andamperage were set to 40 kV and 40 mA respectively. Data was collected atthe Cu wavelength (CuK_(α)=1.5418λ) in the Theta-Theta goniometer from3.0 to 40.0 degrees 2-Theta using a step size of 0.01 degrees and a steptime of 1.0 second. The antiscatter screen was set to a fixed distanceof 1.5 mm. Samples were rotated during data collection. Samples wereprepared by placing them in a silicon low background sample holder androtated during collection. Data were collected using Bruker DIFFRAC Plussoftware and analysis was performed by EVA diffract plus software. ThePXRD data file was not processed prior to peak searching. Using the peaksearch algorithm in the EVA software, peaks selected with a thresholdvalue of 1 were used to make preliminary peak assignments. To ensurevalidity, adjustments were manually made; the output of automatedassignments was visually checked, and peak positions were adjusted tothe peak maximum. Peaks with relative intensity of 3% were generallychosen. Typically, the peaks which were not resolved or were consistentwith noise were not selected. A typical error associated with the peakposition from PXRD stated in USP up to +/−0.2° 2-Theta (USP-941). Onediffraction pattern was consistently observed and is provided in FIG. 1.A list of diffraction peaks expressed in terms of the degree 2θ andrelative intensities with a relative intensity of ≥3.0% of a PXRD from asample obtained by Synthesis 7S-2 is provided above in Table X1.

TABLE X1 Angle(2theta) Relative Intensity(%) 3.7 74.3 7.3 83.3 8.1 12.58.5 6.5 10.1 6.6 13.6 3.5 14.7 49.8 15.2 7.9 15.5 28.7 15.9 18.3 16.960.8 17.4 26.3 17.7 11.4 17.9 13.5 18.9 75.4 19.7 18.7 20.2 100.0 20.924.8 21.5 14.8 22.2 31.7 22.9 10.1 23.5 34.6 23.7 8.2 24.4 6.5 24.9 8.725.2 6.4 25.9 14.7 26.4 48.6 26.7 12.5 27.5 15.8 27.9 6.1 28.3 10.5 29.515.5 29.8 12.6 30.2 12.1 30.9 3.4 31.7 16.4 33.3 17.2 34.0 14.9 35.8 4.837.5 3.2 38.6 5.3

Examples 8 and 92-({4-[2-(4-Cyano-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylicAcid, DIAST-X1 (8) [from C56]; and2-({4-[2-(4-Cyano-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylicAcid, DIAST-X2 (9) [from C57]

Step 1. Synthesis of3-fluoro-4-[2-methyl-4-(piperidin-4-yl)-1,3-benzodioxol-2-yl]benzonitrile,p-toluenesulfonate Salt (C54)

To a solution of P4 (161 mg, 0.367 mmol) in ethyl acetate (8 mL) wasadded p-toluenesulfonic acid (158 mg, 0.919 mmol), and the reactionmixture was stirred at 65° C. for 16 hours. Removal of solvent in vacuoprovided C54 as a dark yellow gum; this material was taken directly intothe next step.

Step 2. Synthesis of methyl2-({4-[2-(4-cyano-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylate(C55)

To a solution of C54 (from the previous step; 50.367 mmol) inacetonitrile (3.7 mL) was added potassium carbonate (219 mg, 1.58 mmol),followed by P15 (115 mg, 0.390 mmol). The reaction mixture was stirredat 50° C. for 20 hours, whereupon it was diluted with ethyl acetate (10mL) and filtered. The filter cake was washed with ethyl acetate (3×10mL), and the combined filtrates were concentrated in vacuo. Silica gelchromatography (Gradient: 0% to 100% ethyl acetate in petroleum ether)afforded C55 as a dark yellow oil. Yield: 191.0 mg, 0.320 mmol, 87% over2 steps. LCMS m/z 619.1 [M+Na⁺].

Step 3. Isolation of methyl2-({4-[2-(4-cyano-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylate,ENT-1 (C56) and methyl2-({4-[2-(4-cyano-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(28)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylate,ENT-2 (C57)

Separation of C55 (191 mg, 0.320 mmol) into its component stereoisomersat the dioxolane was carried out via SFC [Column: Chiral TechnologiesChiralCel OD, 5 μm; Mobile phase: 3:2 carbon dioxide/2-propanol]. Thefirst-eluting isomer, obtained as a white gum, was designated as ENT-1(C56). Yield: 114 mg; this material contained residual ethanol. LCMS m/z597.1 [M+H]⁺. Retention time 4.40 minutes (Column: Chiral TechnologiesChiralCel OD-3, 4.6×100 mm, 3 μm; Mobile phase A: carbon dioxide; Mobilephase B: 2-propanol containing 0.05% diethylamine; Gradient: 5% to 40% Bover 4.5 minutes, then held at 40% B for 2.5 minutes; Flow rate: 2.8mL/minute).

The second-eluting isomer was repurified using SFC [Column: ChiralTechnologies ChiralCel OD, 5 μm; Mobile phase: 55:45 carbondioxide/(2-propanol containing 0.1% ammonium hydroxide)], to afford acolorless gum that was designated as ENT-2 (C57). Yield: 50 mg, 83.8μmol, 26%. LCMS m/z 597.1 [M+H]⁺. Retention time 4.74 minutes(Analytical conditions identical to those used for C56).

Step 4. Synthesis of2-({4-[2-(4-cyano-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(28)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylicacid, DIAST-X1 (8) [from C56]

A solution of C56 (114 mg, 0.191 mmol) in acetonitrile (10 mL) wastreated with an aqueous solution of1,3,4,6,7,8-hexahydro-2H-pyrimido[1,2-a]pyrimidine (0.97 M, 394 μL,0.382 mmol), and the reaction mixture was stirred at room temperaturefor 23 hours. More of the aqueous solution of1,3,4,6,7,8-hexahydro-2H-pyrimido[1,2-a]pyrimidine (0.97 M, 394 μL,0.382 mmol) was added, and stirring was continued for 6 hours, whereuponthe pH was carefully adjusted to 7 to 8 by addition of 1 M hydrochloricacid. After removal of volatiles in vacuo, purification was carried outusing reversed-phase HPLC (Column: Agela Durashell C18, 5 μm; Mobilephase A: 0.05% ammonium hydroxide in water; Mobile phase B:acetonitrile; Gradient: 30% to 50% B) to provide 8 as a white solid.Yield: 22.2 mg, 38.1 μmol, 20%. LCMS m/z 583.3 [M+H]⁺. ¹H NMR (400 MHz,methanol-d₄): δ 8.19 (d, J=1.4 Hz, 1H), 7.94 (dd, J=8.4, 1.5 Hz, 1H),7.77 (dd, J=7.7, 7.7 Hz, 1H), 7.64 (dd, J=10.6, 1.6 Hz, 1H), 7.58 (d,J=8.4 Hz, 1H), 7.57 (dd, J=8.0, 1.5 Hz, 1H), 6.81-6.75 (m, 1H),6.75-6.68 (m, 2H), 5.34-5.25 (m, 1H), 4.73 (dd, J=15.3, 3.0 Hz, 1H),4.67-4.59 (m, 1H), 4.49 (dt, J=9.2, 6.0 Hz, 1H), 3.96 (AB quartet,J_(AB)=13.7 Hz, Δν_(AB)=41.2 Hz, 2H), 3.06 (br d, J=11 Hz, 1H), 2.95 (brd, J=11 Hz, 1H), 2.87-2.76 (m, 1H), 2.71 (tt, J=12.0, 3.9 Hz, 1H),2.61-2.50 (m, 1H), 2.36-2.21 (m, 2H), 2.06 (s, 3H), 1.95-1.72 (m, 4H).

Step 5. Synthesis of2-({4-[2-(4-cyano-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylicAcid, DIAST-X2 (9) [from C57]

A solution of C57 (50 mg, 84 μmol) in acetonitrile (10 mL) was treatedwith an aqueous solution of1,3,4,6,7,8-hexahydro-2H-pyrimido[1,2-a]pyrimidine (0.97 M; 173 μL,0.168 mmol). The reaction was stirred at room temperature (about 25° C.)for 16 hours, whereupon an additional quantity of an aqueous solution of1,3,4,6,7,8-hexahydro-2H-pyrimido[1,2-a]pyrimidine (0.97 M; 173 μL,0.168 mmol) was added, and stirring was continued at 25° C. for 29hours. The reaction mixture was then carefully adjusted to pH 7 to 8 byaddition of 1 M hydrochloric acid; the resulting mixture wasconcentrated in vacuo and subjected to reversed-phase HPLC (Column:Xtimate™ C18, 5 μm; Mobile phase A: 0.05% ammonium hydroxide in water;Mobile phase B: acetonitrile; Gradient: 27% to 67% B), affording 9 as awhite solid. Yield: 18.0 mg, 30.9 μmol, 37%. LCMS m/z 583.3 [M+H]⁺. ¹HNMR (400 MHz, methanol-d₄) δ 8.36-8.33 (m, 1H), 7.97 (dd, J=8.5, 1.5 Hz,1H), 7.78 (dd, J=7.7, 7.7 Hz, 1H), 7.70-7.63 (m, 2H), 7.57 (dd, J=8.0,1.5 Hz, 1H), 6.83-6.76 (m, 1H), 6.76-6.71 (m, 2H), 5.34-5.25 (m, 1H),4.95-4.85 (m, 1H, assumed; partially obscured by water peak), 4.73 (dd,component of ABX pattern, J=15.3, 2.7 Hz, 1H), 4.68-4.60 (m, 1H), 4.50(dt, J=9.2, 6.0 Hz, 1H), 4.02 (AB quartet, J_(AB)=13.8 Hz, Δν_(AB)=48.2Hz, 2H), 3.13 (br d, J=11 Hz, 1H), 3.01 (br d, J=11.5 Hz, 1H), 2.89-2.78(m, 1H), 2.78-2.68 (m, 1H), 2.60-2.50 (m, 1H), 2.45-2.30 (m, 2H), 2.07(br s, 3H), 2.00-1.86 (m, 2H), 1.83 (m, 2H).

Example 102-({4-[2-(5-Chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylicAcid, DIAST-X2 (10) [from P9]

Step 1. Synthesis of5-chloro-2-[2-methyl-4-(piperidin-4-yl)-1,3-benzodioxol-2-yl]pyridine,ENT-X2, p-toluenesulfonate Salt (C58) [from P9]

A solution of P9 (228 mg, 0.529 mmol) in ethyl acetate (2.7 mL) wastreated with p-toluenesulfonic acid monohydrate (116 mg, 0.610 mmol),and the reaction mixture was heated at 50° C. for 16 hours. It was thenallowed to stir at room temperature overnight, whereupon the precipitatewas collected via filtration and rinsed with a mixture of ethyl acetateand heptane (1:1, 2×20 mL) to provide C58 as a white solid. Yield: 227mg, 0.451 mmol, 85%. LCMS m/z 331.0♦ [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆):δ 8.73 (d, J=2.4 Hz, 1H), 8.61-8.46 (br m, 1H), 8.35-8.18 (br m, 1H),8.02 (dd, J=8.5, 2.5 Hz, 1H), 7.64 (d, J=8.5 Hz, 1H), 7.47 (d, J=7.8,2H), 7.11 (d, J=7.8 Hz, 2H), 6.89-6.81 (m, 2H), 6.72 (pentet, J=4.0 Hz,1H), 3.45-3.27 (m, 2H, assumed; partially obscured by water peak),3.10-2.91 (m, 3H), 2.28 (s, 3H), 2.02 (s, 3H), 1.97-1.80 (m, 4H).

Step 2. Synthesis of methyl2-({4-[2-(5-chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylate,DIAST-Y2 (C59) [from P9]

N,N-Diisopropylethylamine (0.234 mL, 1.34 mmol) was added to a solutionof C58 (225 mg, 0.447 mmol) in acetonitrile (2.2 mL). After this mixturehad been stirred for 5 minutes at 45° C., P15 (120 mg, 0.407 mmol) wasadded, and stirring was continued at 45° C. for 16 hours, whereupon P15(11 mg, 37 μmol) was again added. After an additional 3 hours ofstirring, the reaction mixture was treated with water (2.5 mL) andallowed to cool to room temperature. More water (5 mL) was added, andthe resulting slurry was stirred for 2 hours, whereupon the solid wascollected via filtration and washed with a mixture of acetonitrile andwater (15:85, 3×5 mL) to afford C59 as an off-white solid (252 mg). Thismaterial contained some N,N-diisopropylethylamine by ¹H NMR analysis,and was taken directly to the following step. LCMS m/z 589.1♦ [M+H]⁺. ¹HNMR (400 MHz, chloroform-d) 8.61 (d, J=2.3 Hz, 1H), 8.18 (d, J=1.5 Hz,1H), 7.96 (dd, J=8.5, 1.5 Hz, 1H), 7.74 (d, J=8.5 Hz, 1H), 7.67 (dd,component of ABX pattern, J=8.4, 2.4 Hz, 1H), 7.59-7.51 (m, 1H),6.82-6.75 (m, 1H), 6.74-6.66 (m, 2H), 5.28-5.19 (m, 1H), 4.75 (dd,component of ABX pattern, J=15.3, 6.0 Hz, 1H), 4.68 (dd, component ofABX pattern, J=15.3, 3.4 Hz, 1H), 4.67-4.58 (m, 1H), 4.41 (ddd, J=9.1,5.9, 5.9 Hz, 1H), 3.95 (s, 2H), 3.95 (s, 3H), 3.07-2.89 (m, 2H),2.81-2.69 (m, 2H), 2.53-2.41 (m, 1H), 2.37-2.22 (m, 2H), 2.05 (s, 3H),1.93-1.74 (m, 4H).

Step 3. Synthesis of2-({4-[2-(5-chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylicAcid, DIAST-X2 (10) [from P9]

A suspension of C59 (from the previous step; 250 mg, 50.407 mmol) inmethanol (2 mL) was heated to 40° C., whereupon aqueous sodium hydroxidesolution (1 M; 0.81 mL, 0.81 mmol) was added. After 17 hours, thereaction mixture was allowed to cool to room temperature, and the pH wasadjusted to 5 to 6 with 1 M aqueous citric acid solution. The resultingmixture was diluted with water (2 mL), stirred for 2 hours, andextracted with ethyl acetate (3×5 mL); the combined organic layers werewashed with saturated aqueous sodium chloride solution (5 mL), driedover sodium sulfate, filtered, and concentrated in vacuo to provide afoamy solid. This material was taken up in a mixture of ethyl acetateand heptane (1:1, 4 mL), heated to 50° C., and then allowed to cool andstir overnight. Filtration afforded 10 as a white solid. Yield: 179 mg,0.311 mmol, 76% over 2 steps. LCMS m/z 575.1♦ [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆) δ 12.73 (br s, 1H), 8.71 (d, J=2.5 Hz, 1H), 8.27 (d, J=1.5 Hz,1H), 8.00 (dd, J=8.5, 2.5 Hz, 1H), 7.80 (dd, J=8.4, 1.6 Hz, 1H), 7.64(d, J=8.4 Hz, 1H), 7.60 (d, J=8.5 Hz, 1H), 6.83-6.72 (m, 3H), 5.14-5.06(m, 1H), 4.77 (dd, component of ABX pattern, J=15.2, 7.2 Hz, 1H), 4.63(dd, component of ABX pattern, J=15.2, 2.8 Hz, 1H), 4.50-4.42 (m, 1H),4.37 (ddd, J=9.0, 5.9, 5.9 Hz, 1H), 3.85 (AB quartet, J_(AB)=13.6 Hz,Δν_(AB)=71.5 Hz, 2H), 3.01 (br d, J=11.2 Hz, 1H), 2.85 (br d, J=11.2 Hz,1H), 2.74-2.57 (m, 2H), 2.47-2.38 (m, 1H), 2.29-2.10 (m, 2H), 2.01 (s,3H), 1.81-1.64 (m, 4H).

Synthesis 10S-1. Synthesis of Example 10,1,3-dihydroxy-2-(hydroxymethyl)propan-2-aminium Salt Synthesis of1,3-dihydroxy-2-(hydroxymethyl)propan-2-aminium2-({4-[2-(5-chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylate,DIAST-X2 (10, 1,3-dihydroxy-2-(hydroxymethyl)propan-2-aminium salt)[from P9].

A mixture of 10 (1.54 g, 2.68 mmol) in tetrahydrofuran (10 mL) wastreated with an aqueous solution of2-amino-2-(hydroxymethyl)propane-1,3-diol (Tris, 1.0 M; 2.81 mL, 2.81mmol). After 24 hours, the reaction mixture was concentrated in vacuowith ethanol (2×50 mL). The residue was treated with ethanol (15 mL).After stirring for 20 hours, the solid was collected via filtration andwashed with cold ethanol (5 mL) to afford 10,1,3-dihydroxy-2-(hydroxymethyl)propan-2-aminium salt as a white solid.Yield: 1.41 g, 2.03 mmol, 76%. LCMS m/z 575.3♦ [M+H]⁺. ¹H NMR (600 MHz,DMSO-d₆) δ 8.71 (d, J=2.5 Hz, 1H), 8.21 (br s, 1H), 8.00 (dd, J=8.5, 2.5Hz, 1H), 7.79 (br d, J=8.4 Hz, 1H), 7.60 (d, J=8.5 Hz, 1H), 7.57 (d,J=8.4 Hz, 1H), 6.82-6.73 (m, 3H), 5.13-5.07 (m, 1H), 4.74 (dd, J=15.3,7.2 Hz, 1H), 4.61 (dd, J=15.3, 2.9 Hz, 1H), 4.49-4.43 (m, 1H), 4.37(ddd, J=9.0, 5.9, 5.9 Hz, 1H), 3.93 (d, J=13.6 Hz, 1H), 3.75 (d, J=13.5Hz, 1H), 3.01 (br d, J=11.3 Hz, 1H), 2.86 (br d, J=11.4 Hz, 1H),2.73-2.59 (m, 2H), 2.48-2.37 (m, 1H), 2.27-2.20 (m, 1H), 2.19-2.12 (m,1H), 2.01 (s, 3H), 1.82-1.66 (m, 4H). mp=184° C. to 190° C.

Synthesis 10S-2. Alternative synthesis of Example 10,1,3-dihydroxy-2-(hydroxymethyl)propan-2-aminium Salt

A mixture of 10 (8.80 gm, 15.3 mmol) in 2-methyltetrahydrofuran (90 ml)was concentrated in vacuo on a rotary evaporator, in a 37° C. waterbath, to reduce the total volume to −54 ml. Isopropanol (90 ml) wasadded to the mixture and then again concentrate the resulting mixture toa volume of −54 ml. Isopropanol (135 ml) was added to the mixture,followed by addition of aqueous tris amine (3M; 5.0 ml, 0.98 equiv). Theresulting mixture/solution was stirred at ambient temperature; and asolid precipitate began to form within −15 min. The mixture was thenstirred at ambient temperature for additional 5 hr. The resultingmixture/slurry was cooled to 0° C. and the cooled slurry was stirred forabout another 2 hr. The slurry was filtered and washed with coldisopropanol (3×15 ml). The solid collected was allowed to Air dry on thecollection funnel for about 90 min and then transfer to the vacuum ovenfor overnight drying. After ˜16 hr at 50° C./23inHg vacuum (with aslight nitrogen bleed) 8.66 gm of 10,1,3-dihydroxy-2-(hydroxymethyl)propan-2-aminium salt was obtained aswhite solid; 99.8 area % by UPLC (yield: 12.5 mmol, 81%). LCMS and ¹HNMR data were obtained, which are substantially the same as those inSynthesis 10S-1 shown above.

Acquisition of Powder X-Ray Diffraction (PXRD) Data for Form a ofExample 10, 1,3-dihydroxy-2-(hydroxymethyl)propan-2-Aminium Salt (AlsoKnown as Form A of Anhydrous Tris Salt of Compound Example 10)

The white solid of the tris salt of Example 10 (from both Synthesis10S-1 and Synthesis 10S-2) was submitted for PXRD analysis and found tobe a crystalline material (which is designated as Form A). Powder X-raydiffraction analysis was conducted using a Bruker AXS D8 Endeavordiffractometer equipped with a Cu radiation source. The divergence slitwas set at 15 mm continuous illumination. Diffracted radiation wasdetected by a PSD-Lynx Eye detector, with the detector PSD opening setat 2.99 degrees. The X-ray tube voltage and amperage were set to 40 kVand 40 mA respectively. Data was collected at the Cu wavelength(CuK_(α)=1.5418λ) in the Theta-Theta goniometer from 3.0 to 40.0 degrees2-Theta using a step size of 0.01 degrees and a step time of 1.0 second.The antiscatter screen was set to a fixed distance of 1.5 mm. Sampleswere rotated during data collection. Samples were prepared by placingthem in a silicon low background sample holder and rotated duringcollection. Data were collected using Bruker DIFFRAC Plus software andanalysis was performed by EVA diffract plus software. The PXRD data filewas not processed prior to peak searching. Using the peak searchalgorithm in the EVA software, peaks selected with a threshold value of1 were used to make preliminary peak assignments. To ensure validity,adjustments were manually made; the output of automated assignments wasvisually checked, and peak positions were adjusted to the peak maximum.Peaks with relative intensity of 3% were generally chosen. Typically,the peaks which were not resolved or were consistent with noise were notselected. A typical error associated with the peak position from PXRDstated in USP up to +/−0.2° 2-Theta (USP-941). A list of diffractionpeaks expressed in terms of the degree 2θ and relative intensities witha relative intensity of 3.0% of a PXRD from a sample obtained bySynthesis 10S-2 is provided above in Table X2.

TABLE X2 Angle(2 theta) Relative Intensity(%) 3.9 18.4 7.7 36.3 8.1 10.48.7 3.4 10.2 4.1 14.6 5.8 15.2 30.1 15.7 45.5 16.0 31.3 16.8 8.7 17.686.0 19.2 46.6 19.5 25.4 19.8 31.4 20.2 25.0 21.1 100.0 21.4 40.2 22.237.0 23.0 19.8 24.3 43.0 25.0 9.9 26.0 15.8 27.3 35.3 28.2 14.1 29.319.7 29.8 11.7 31.6 9.3 32.8 6.0 34.0 14.4 34.5 12.1 35.4 3.0 36.5 4.1

Example 111-(2-Methoxyethyl)-2-({4-[2-methyl-2-(pyridin-3-yl)-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1H-benzimidazole-6-carboxylicAcid, Formate Salt (11)

This entire synthetic sequence was carried out in library format.

Step 1. Synthesis of methyl1-(2-methoxyethyl)-2-({4-[2-methyl-2-(pyridin-3-yl)-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1H-benzimidazole-6-carboxylate(C60)

A mixture of P14 (44 mg, 100 μmol) and 3-ethynylpyridine (21 mg, 200μmol) in toluene (800 μL) was treated with sodium bicarbonate (100μmol), followed by triruthenium dodecacarbonyl (6 mg, 9 μmol). Thereaction vial was then capped and shaken at 120° C. for 16 hours.Removal of solvent using a Speedvac® concentrator provided C60, whichwas taken directly into the following step.

Step 2. Synthesis of1-(2-methoxyethyl)-2-({4-[2-methyl-2-(pyridin-3-yl)-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1H-benzimidazole-6-carboxylicAcid, Formate Salt (11)

An aqueous solution of sodium hydroxide (1.0 M; 200 μL, 200 μmol) wasadded to a solution of C60 (from the previous step, 5100 μmol) in amixture of methanol (400 μL) and tetrahydrofuran (400 μL). The reactionvial was capped and shaken at 80° C. for 16 hours, whereupon thereaction mixture was evaporated using a Speedvac concentrator, andpurified using reversed-phase HPLC (Column: Agela Durashell C18, 5 μm;Mobile phase A: 0.225% formic acid in water; Mobile phase B:acetonitrile; Gradient: 12% to 52% B) to afford 11. Yield: 2.2 mg, 4.2μmol, 4% over 2 steps. LCMS m/z 529 [M+H]⁺. Retention time: 2.47 minutes(Column: Waters XBridge C18, 2.1×50 mm, 5 μm; Mobile phase A: 0.0375%trifluoroacetic acid in water; Mobile phase B: 0.01875% trifluoroaceticacid in acetonitrile; Gradient: 1% to 5% B over 0.6 minutes; 5% to 100%B over 3.4 minutes; Flow rate: 0.8 mL/minute).

Example 122-({4-[2-(4-Chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[2-(dimethylamino)ethyl]-1H-benzimidazole-6-carboxylicAcid (12)

This entire synthetic sequence was carried out in library format.

Step 1. Synthesis of methyl3-{[2-(dimethylamino)ethyl]amino}-4-nitrobenzoate (C61)

Methyl 3-fluoro-4-nitrobenzoate (0.2 M solution inN,N-dimethylformamide; 1 mL, 200 μmol) was treated withN,N-dimethylethane-1,2-diamine (18 mg, 200 μmol) andN,N-diisopropylethylamine (78 mg, 600 μmol). The reaction vial was thencapped and shaken at 50° C. for 16 hours, whereupon the reaction mixturewas evaporated using a Speedvac® concentrator to afford C61. Thismaterial was taken directly to the following step.

Step 2. Synthesis of methyl4-amino-3-{[2-(dimethylamino)ethyl]amino}benzoate (C62)

Zinc dust was activated using dilute hydrochloric acid. Methanol (2 mL)was added to C61 (from the previous step, 5200 μmol), followed by anaqueous solution of calcium chloride (1.0 M; 200 μL, 200 μmol) and theactivated zinc dust (130 mg, 2.0 mmol). The reaction vial was capped andshaken at 70° C. for 16 hours, whereupon the reaction mixture wasfiltered. The filtrate was concentrated using a Speedvac® concentrator,and the residue was taken up in water (2 mL) and then extracted withethyl acetate (2×3 mL). The combined organic layers were evaporatedusing a Speedvac® concentrator to afford C62 (estimated to be 150 μmol),which was used directly in the next step.

Step 3. Synthesis of methyl4-[({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}acetyl)amino]-3-{[2-(dimethylamino)ethyl]amino}benzoate(C63)

Compound P10 (41 mg, 100 μmol) was added to C62 (from the previous step,approximately 150 μmol), and the mixture was treated with anN,N-dimethylacetamide solution of 2-hydroxypyridine 1-oxide and1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.1 M ineach; 1 mL, 100 μmol of each). N,N-Diisopropylethylamine (39 mg, 300μmol) was then added, and the reaction vial was capped and shaken at 50°C. for 16 hours. The reaction mixture was then concentrated using aSpeedvac concentrator and purified using preparative thin-layerchromatography to provide C63, which was advanced directly to thefollowing step.

Step 4. Synthesis of methyl2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[2-(dimethylamino)ethyl]-1H-benzimidazole-6-carboxylate(C64)

A mixture of acetic acid (500 μL) and C63 (from the previous step, 5100μmol) was shaken in a capped vial at 150° C. for 2 hours, whereupon thereaction mixture was evaporated using a Speedvac® concentrator. Theresulting C64 was advanced directly to the following step.

Step 5. Synthesis of2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[2-(dimethylamino)ethyl]-1H-benzimidazole-6-carboxylicAcid (12)

A solution of C64 (from the previous step, 5100 μmol) in ethanol (500μL) was treated with an aqueous solution of lithium hydroxide (2.0 M;500 μL, 1 mmol), and the reaction mixture was shaken at 50° C. for 2hours in a sealed vial. After the pH of the mixture had been adjusted to7 by addition of 1.0 M hydrochloric acid, the resulting mixture wasconcentrated using a Speedvac® concentrator, and then purified viareversed-phase HPLC [Column: Agela Durashell C18, 5 μm; Mobile phase A:ammonium hydroxide in water (pH 10); Mobile phase B: acetonitrile;Gradient: 25% to 65% B] to afford 12. Yield: 7.0 mg, 12 μmol, 12% over 3steps. LCMS m/z 593 [M+H]⁺. Retention time: 2.45 minutes (Column: WatersXBridge C18, 2.1×50 mm, 5 μm; Mobile phase A: 0.0375% trifluoroaceticacid in water; Mobile phase B: 0.01875% trifluoroacetic acid inacetonitrile; Gradient: 10% to 100% B over 4.0 minutes; Flow rate: 0.8mL/minute).

Example 132-({4-[2-(4-Chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-3-(1,3-oxazol-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylicAcid (13)

Step 1. Synthesis of methyl6-[(1,3-oxazol-2-ylmethyl)amino]-5-nitropyridine-2-carboxylate (C65)

Triethylamine (532 mg, 5.26 mmol) was added to a suspension of1-(1,3-oxazol-2-yl)methanamine, hydrochloride salt (236 mg, 1.75 mmol)and methyl 6-chloro-5-nitropyridine-2-carboxylate (386 mg, 1.78 mmol) intetrahydrofuran (5 mL). After the reaction mixture had been stirred at25° C. for 14 hours, it was poured into water (30 mL) and extracted withdichloromethane (2×50 mL). The combined organic layers were dried overmagnesium sulfate, filtered, and concentrated in vacuo; silica gelchromatography (Gradient: 0% to 5% methanol in dichloromethane) affordedC65 as a yellow solid. Yield: 310 mg, 1.11 mmol, 63%. LCMS m/z 278.7[M+H]⁺. ¹H NMR (400 MHz, chloroform-d) δ 8.69-8.61 (br m, 1H), 8.58 (d,J=8.4 Hz, 1H), 7.65 (d, J=0.8 Hz, 1H), 7.46 (d, J=8.4 Hz, 1H), 7.11 (d,J=1.0 Hz, 1H), 5.07 (d, J=5.3 Hz, 2H), 3.97 (s, 3H).

The remainder of this synthetic sequence was carried out in libraryformat.

Step 2. Synthesis of methyl5-amino-6-[(1,3-oxazol-2-ylmethyl)amino]pyridine-2-carboxylate (C66)

Aqueous ammonium chloride solution (5.0 M; 400 μL, 2.0 mmol), followedby activated zinc (131 mg, 2.0 mmol), was added to a solution of C65 (56mg, 200 μmol) in methanol (2.0 mL). The reaction vial was then cappedand shaken at 30° C. for 16 hours, whereupon the reaction mixture wasfiltered. The filtrate was concentrated using a Speedvac concentrator,then mixed with water (1.0 mL) and extracted with dichloromethane (3×1.0mL); the combined organic layers were evaporated using a Speedvac®concentrator to provide C66, which was taken directly into the followingstep.

Step 3. Synthesis of methyl5-[({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}acetyl)amino]-6-[(1,3-oxazol-2-ylmethyl)amino]pyridine-2-carboxylate(C67)

A mixture of P10 (81 mg, 200 μmol) and C66 (from the previous step, 5200μmol) was mixed with N,N-dimethylacetamide and then treated withN,N-diisopropylethylamine (100 μL, 600 μmol). A solution containing1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.24 M)and 2-hydroxypyridine 1-oxide (0.1 M) in N,N-dimethylacetamide (1.0 mL,containing 240 μmol 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimidehydrochloride and 100 μmol 2-hydroxypyridine 1-oxide) was added, and thereaction vial was capped and shaken at 50° C. for 16 hours. Volatileswere then removed using a Speedvac® concentrator, and the residue wassubjected to preparative thin-layer chromatography to afford C67, whichwas advanced directly to the next step.

Step 4. Synthesis of methyl2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-3-(1,3-oxazol-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate(C68)

A mixture of acetic acid (1.0 mL) and C67 (from the previous step, 5200μmol) was shaken at 150° C. for 2 hours, whereupon the reaction mixturewas evaporated using a Speedvac® concentrator. The resulting C68 wasused directly in the following step.

Step 5. Synthesis of2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-3-(1,3-oxazol-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylicacid (13)

Aqueous lithium hydroxide solution (2.0 M; 1.0 mL, 2.0 mmol) was addedto a mixture of C68 (from the previous step, 5200 μmol) intetrahydrofuran (1.0 mL). After addition of methanol (500 μL), thereaction vial was capped and shaken at 50° C. for 16 hours. Afterremoval of volatiles using a Speedvac® concentrator, dimethyl sulfoxide(1.0 mL) was added, and the pH was adjusted to 7 to 8 with concentratedhydrochloric acid. The resulting mixture was purified usingreversed-phase HPLC [Column: Agela Durashell C18, 5 μm; Mobile phase A:ammonium hydroxide in water (pH 10); Mobile phase B: acetonitrile;Gradient: 24% to 64% B] to afford 13. Yield: 3.9 mg, 6.5 μmol, 3% over 4steps. LCMS m/z 604 [M+H]⁺. Retention time: 3.14 minutes (Column: WatersXBridge C18, 2.1×50 mm, 5 μm; Mobile phase A: 0.0375% trifluoroaceticacid in water; Mobile phase B: 0.01875% trifluoroacetic acid inacetonitrile; Gradient: 1% to 5% B over 0.6 minutes; 5% to 100% B over3.4 minutes; Flow rate: 0.8 mL/minute).

Example 142-({4-[(2)-2-(4-Chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-methyl-1H-benzimidazole-6-carboxylicAcid (14)

Step 1. Synthesis of methyl2-({4-[(2)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-methyl-1H-benzimidazole-6-carboxylate(C69)

N,N-Diisopropylethylamine (683 μL, 3.92 mmol), was added to a mixture ofP3 (680 mg, 1.31 mmol) in acetonitrile (5.2 mL); this was allowed tostir for 5 minutes at 45° C., whereupon P16 (319 mg, 1.34 mmol) wasadded. Stirring was continued at 45° C. for 2.75 hours, and then water(6 mL) was added before allowing the reaction mixture to cool to roomtemperature and stir for 30 minutes. Solids were collected viafiltration and washed with a mixture of acetonitrile and water (1:4, 3×5mL) to afford C69 as a white solid. Yield: 635 mg, 1.15 mmol, 88%. LCMSm/z 550.1♦ [M+H]⁺. ¹H NMR (400 MHz, chloroform-d) δ 8.15-8.12 (m, 1H),7.97 (dd, J=8.5, 1.6 Hz, 1H), 7.74 (d, J=8.5 Hz, 1H), 7.50 (dd, J=8.2,8.2 Hz, 1H), 7.16-7.07 (m, 2H), 6.79-6.73 (m, 1H), 6.72-6.65 (m, 2H),3.98 (s, 3H), 3.96 (s, 3H), 3.88 (s, 2H), 3.04-2.93 (m, 2H), 2.76-2.66(m, 1H), 2.37-2.25 (m, 2H), 2.04 (br s, 3H), 1.89-1.78 (m, 4H).

Step 2. Synthesis of2-({4-[(2)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-methyl-1H-benzimidazole-6-carboxylicacid (14)

A mixture of C69 (600 mg, 1.09 mmol) in methanol (11 mL) was heated to45° C., and then treated with aqueous sodium hydroxide solution (1 M;2.2 mL, 2.2 mmol). After 24 hours, the reaction mixture was adjusted topH 5 to 6 via addition of aqueous citric acid (1 M; 1.1 mL), and thendiluted with water (10 mL). The resulting mixture was allowed to cool toroom temperature and stir for 1 hour, whereupon the precipitated solidwas collected via filtration and washed with a mixture of methanol andwater (1:4; 3×5 mL). This afforded 14 as a white solid. Yield: 535 mg,0.998 mmol, 92%. LCMS m/z 536.1♦ [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ8.16 (d, J=1.5 Hz, 1H), 7.81 (dd, J=8.4, 1.6 Hz, 1H), 7.64 (d, J=8.4 Hz,1H), 7.59-7.52 (m, 2H), 7.33 (dd, J=8.3, 2.1 Hz, 1H), 6.81-6.70 (m, 3H),3.94 (s, 3H), 3.84 (s, 2H), 3.01-2.91 (m, 2H), 2.70-2.59 (m, 1H),2.28-2.16 (m, 2H), 2.02 (s, 3H), 1.73 (m, 4H).

Examples 15 and 162-{6-[2-(4-Chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]-6-azaspiro[2.5]oct-1-yl}-1-(2-methoxyethyl)-1H-benzimidazole-6-carboxylicacid, DIAST-X1, trifluoroacetate salt (15) [from P18 via C71]; and2-{6-[2-(4-Chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]-6-azaspiro[2.5]oct-1-yl}-1-(2-methoxyethyl)-1H-benzimidazole-6-carboxylicAcid, DIAST-X2, trifluoroacetate Salt (16) [from P18 Via C72]

Step 1. Synthesis of methyl2-{6-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]-6-azaspiro[2.5]oct-1-yl}-1-(2-methoxyethyl)-1H-benzimidazole-6-carboxylate(C70) [from P18]

A mixture of P18 (240 mg, 0.699 mmol), C4 (275 mg, 0.800 mmol), cesiumcarbonate (455 mg, 1.40 mmol), tris(dibenzylideneacetone)dipalladium(0)(40.0 mg, 43.7 μmol), and1,1′-binaphthalene-2,2′-diylbis(diphenylphosphane) (BINAP; 52.2 mg, 83.8μmol) in toluene (5 mL) was degassed with nitrogen for 5 minutes andthen stirred at 90° C. for 16 hours. The reaction mixture was filtered,and the filtrate was concentrated in vacuo; preparative thin-layerchromatography (Eluent: 1:1 petroleum ether/ethyl acetate) afforded C70,a mixture of diastereomers, as a yellow oil. Yield: 165 mg, 0.272 mmol,39%. LCMS m/z 628.1♦ [M+Na⁺].

Step 2. Isolation of methyl2-{6-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]-6-azaspiro[2.5]oct-1-yl}-1-(2-methoxyethyl)-1H-benzimidazole-6-carboxylate,DIAST-Y1 (C71) [from P18]; and methyl2-{6-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]-6-azaspiro[2.5]oct-1-yl}-1-(2-methoxyethyl)-1H-benzimidazole-6-carboxylate,DIAST-Y2 (C72) [from P18]

Separation of the stereoisomers at the dioxolane in C70 (165 mg, 0.272mmol) was carried out using SFC [Column: Chiral Technologies ChiralpakAD, 10 μm; Mobile phase: 65:35 carbon dioxide/(ethanol containing 0.1%ammonium hydroxide)]. The first-eluting isomer was designated asDIAST-Y1 (C71), and the second-eluting isomer as DIAST-Y2 (C72); bothwere isolated as white solids.

C71 Yield: 55.0 mg, 90.7 μmol, 33%. LCMS m/z 605.9♦ [M+H]⁺. Retentiontime 4.47 minutes (Column: Chiral Technologies Chiralpak AD-3, 4.6×100mm, 3 μm; Mobile phase A: carbon dioxide; Mobile phase B: ethanolcontaining 0.05% diethylamine; Gradient: 5% to 40% B over 4.5 minutes,then held at 40% B for 2.5 minutes; Flow rate: 2.8 mL/minute).

C72 Yield: 58.0 mg, 95.7 μmol, 35%. LCMS m/z 628.0♦ [M+Na⁺]. Retentiontime 4.88 minutes (Analytical conditions identical to those used forC71).

Step 3. Synthesis of2-{6-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]-6-azaspiro[2.5]oct-1-yl}-1-(2-methoxyethyl)-1H-benzimidazole-6-carboxylicacid, DIAST-X1, trifluoroacetate Salt (15) [from P18 Via C71]

To a solution of C71 (55.0 mg, 90.7 μmol) in a mixture of methanol (2.0mL) and tetrahydrofuran (1.0 mL) was added an aqueous solution of sodiumhydroxide (3 M; 1.0 mL, 3.0 mmol). After the reaction mixture had beenstirred at 20° C. for 2 hours, the pH was adjusted to 7 by addition of 1M hydrochloric acid, and the resulting mixture was extracted with amixture of dichloromethane and methanol (10:1, 3×30 mL). The combinedorganic layers were dried over magnesium sulfate, filtered, andconcentrated in vacuo. Reversed-phase HPLC (Column: Boston Green ODS, 5μm; Mobile phase A: 0.1% trifluoroacetic acid in water; Mobile phase B:acetonitrile; Gradient: 10% to 95% B) provided 15 as a white solid.Yield: 35.8 mg, 50.7 μmol, 56%. LCMS m/z 592.3♦ [M+H]⁺. ¹H NMR (400 MHz,methanol-d₄) δ 8.46 (s, 1H), 8.21 (d, J=8.6 Hz, 1H), 7.78 (d, J=8.6 Hz,1H), 7.54 (dd, J=8.3, 8.3 Hz, 1H), 7.16-7.08 (m, 2H), 6.76 (dd, J=8.2,8.1 Hz, 1H), 6.55-6.47 (m, 2H), 4.9-4.70 (m, 2H, assumed; partiallyobscured by water peak), 3.82 (t, J=4.9 Hz, 2H), 3.66-3.56 (m, 1H),3.50-3.41 (m, 1H), 3.19-3.09 (m, 1H), 3.15 (s, 3H), 3.08-2.99 (m, 1H),2.63-2.57 (m, 1H), 2.27-2.17 (m, 1H), 2.01 (s, 3H), 1.76-1.66 (m, 2H),1.62-1.50 (m, 2H), 1.35-1.26 (m, 1H).

Step 4. Synthesis of2-{6-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]-6-azaspiro[2.5]oct-1-yl}-1-(2-methoxyethyl)-1H-benzimidazole-6-carboxylicacid, DIAST-X2, trifluoroacetate salt (16) [from P18 Via C72]

To a solution of C72 (58.0 mg, 95.7 μmol) in a mixture of methanol (2.0mL) and tetrahydrofuran (1.0 mL) was added an aqueous solution of sodiumhydroxide (3 M; 1.0 mL, 3.0 mmol). After the reaction mixture had beenstirred at 20° C. for 2 hours, the pH was adjusted to 7 by addition of 1M hydrochloric acid, and the resulting mixture was extracted with amixture of dichloromethane and methanol (10:1, 3×30 mL). The combinedorganic layers were dried over magnesium sulfate, filtered, andconcentrated in vacuo. Reversed-phase HPLC (Column: Boston Green ODS, 5μm; Mobile phase A: 0.1% trifluoroacetic acid in water; Mobile phase B:acetonitrile; Gradient: 35% to 95% B) provided 16 as a white solid.Yield: 33.4 mg, 47.3 μmol, 49%. LCMS m/z 592.2♦ [M+H]⁺. ¹H NMR (400 MHz,methanol-d₄) δ 8.53-8.50 (m, 1H), 8.25 (dd, J=8.6, 1.4 Hz, 1H), 7.80 (brd, J=8.6 Hz, 1H), 7.57 (dd, J=8.4, 8.2 Hz, 1H), 7.25 (dd, J=10.8, 2.0Hz, 1H), 7.19 (br dd, J=8.4, 2.1 Hz, 1H), 6.77 (dd, J=8.2, 8.1 Hz, 1H),6.55-6.50 (m, 2H), 4.9-4.72 (m, 2H, assumed; partially obscured by waterpeak), 3.93-3.80 (m, 2H), 3.68-3.58 (m, 1H), 3.41-3.3 (m, 1H, assumed;partially obscured by solvent peak), 3.25 (s, 3H), 3.22-3.12 (m, 1H),3.07-2.97 (m, 1H), 2.67 (dd, J=8.3, 5.8 Hz, 1H), 2.28-2.17 (m, 1H), 2.01(d, J=1.0 Hz, 3H), 1.86-1.71 (m, 2H), 1.69-1.56 (m, 2H), 1.36-1.26 (m,1H).

Examples 17 and 18 Ammonium2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(1-ethyl-1H-imidazol-5-yl)methyl]-1H-benzimidazole-6-carboxylate,ENT-1 (17) and Ammonium2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(1-ethyl-1H-imidazol-5-yl)methyl]-1H-benzimidazole-6-carboxylate,ENT-2 (18)

Step 1. Synthesis of methyl4-[({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}acetyl)amino]-3-{[(1-ethyl-1H-imidazol-5-yl)methyl]amino}benzoate(C73)

O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (566 mg, 1.49 mmol) was added to a mixture of P19(340 mg, 1.24 mmol) in N,N-dimethylformamide (10 mL), and the mixturewas stirred at 25° C. for 10 minutes. A solution of P10 (503 mg, 1.24mmol) and N,N-diisopropylethylamine (615 μL, 3.53 mmol) inN,N-dimethylformamide (7.7 mL) was then added, and the reaction mixturewas stirred at 25° C. for 16 hours, whereupon it was poured into water(10 mL) and extracted with ethyl acetate (3×50 mL). The combined organiclayers were washed sequentially with aqueous ammonium chloride solution(3×20 mL) and saturated aqueous sodium chloride solution (2×20 mL),dried over sodium sulfate, filtered, and concentrated in vacuo. Uponpurification using silica gel chromatography (Gradient: 0% to 5%methanol in ethyl acetate), C73 was obtained as a pale brown gum. Yield:316 mg, 0.477 mmol, 38%. LCMS m/z 662.2♦ [M+H]⁺.

Step 2. Synthesis of methyl2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(1-ethyl-1H-imidazol-5-yl)methyl]-1H-benzimidazole-6-carboxylate(C74)

A solution of C73 (316 mg, 0.477 mmol) in acetic acid (14 mL) wasstirred at 55° C. for 16 hours. Solvent was removed under high vacuum,and the residue was purified using preparative thin-layer chromatography(Eluent: 10:1 dichloromethane/methanol) to afford C74 as a colorlessoil. Yield: 200 mg, 0.310 mmol, 65%. LCMS m/z 644.3♦ [M+H]⁺.

Step 3. Synthesis of ammonium2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(1-ethyl-1H-imidazol-5-yl)methyl]-1H-benzimidazole-6-carboxylate,ENT-1 (17) and ammonium2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(1-ethyl-1H-imidazol-5-yl)methyl]-1H-benzimidazole-6-carboxylate,ENT-2 (18)

A mixture of C74 (150 mg, 0.233 mmol) and aqueous sodium hydroxidesolution (2 M; 233 μL, 0.466 mmol) in a mixture of methanol (3 mL) andtetrahydrofuran (3 mL) was stirred at 45° C. for 16 hours. After thereaction mixture had been adjusted to pH 7 by addition of 1 Mhydrochloric acid, it was concentrated in vacuo to afford a mixture of17 and 18. These enantiomers were separated via SFC [Column: ChiralTechnologies ChiralCel OD, 10 μm; Mobile phase: 1:1 carbondioxide/(ethanol containing 0.1% ammonium hydroxide)]. The first-elutingenantiomer was designated as ENT-1 (17), and the second-elutingenantiomer as ENT-2 (18); both were isolated as white solids. 17 Yield:45.0 mg, 69.5 μmol, 30%. LCMS m/z 630.3♦ [M+H]⁺. ¹H NMR (400 MHz,methanol-d₄) δ 8.15 (br s, 1H), 8.00 (br d, J=8.4 Hz, 1H), 7.81 (s, 1H),7.72 (d, J=8.2 Hz, 1H), 7.56 (dd, J=8.3, 8.3 Hz, 1H), 7.28 (dd, J=10.9,2.0 Hz, 1H), 7.21 (dd, J=8.3, 2.1 Hz, 1H), 6.77 (dd, component of ABCpattern, J=8.0, 7.7 Hz, 1H), 6.69 (dd, component of ABC pattern, J=7.8,1.2 Hz, 1H), 6.67-6.60 (m, 2H), 5.82 (s, 2H), 4.12 (q, J=7.2 Hz, 2H),3.89 (AB quartet, J_(AB)=14.3 Hz, Δν_(AB)=6.9 Hz, 2H), 3.00-2.90 (m,2H), 2.74-2.64 (m, 1H), 2.32-2.21 (m, 2H), 2.02 (s, 3H), 1.82-1.61 (m,4H), 1.29 (t, J=7.3 Hz, 3H). Retention time 5.66 minutes (Column: ChiralTechnologies Chiralpak AD-3, 4.6×150 mm, 3 μm; Mobile phase A: carbondioxide; Mobile phase B: methanol containing 0.05% diethylamine;Gradient: 5% to 40% B over 5.5 minutes, then held at 40% B for 3.0minutes; Flow rate: 2.5 mL/minute).

18 Yield: 32.8 mg, 50.7 μmol, 22%. LCMS m/z 630.3♦ [M+H]⁺. ¹H NMR (400MHz, methanol-d₄) δ 8.15 (s, 1H), 8.00 (d, J=8.5 Hz, 1H), 7.81 (s, 1H),7.72 (d, J=8.5 Hz, 1H), 7.56 (dd, J=8.3, 8.3 Hz, 1H), 7.28 (dd, J=10.9,2.0 Hz, 1H), 7.21 (dd, J=8.3, 2.0 Hz, 1H), 6.77 (dd, component of ABCpattern, J=7.8, 7.8 Hz, 1H), 6.69 (dd, component of ABC pattern, J=7.9,1.2 Hz, 1H), 6.67-6.60 (m, 2H), 5.82 (s, 2H), 4.12 (q, J=7.3 Hz, 2H),3.89 (AB quartet, J_(AB)=14.1 Hz, Δν_(AB)=7.4 Hz, 2H), 3.01-2.90 (m,2H), 2.74-2.63 (m, 1H), 2.31-2.21 (m, 2H), 2.02 (s, 3H), 1.82-1.60 (m,4H), 1.29 (t, J=7.3 Hz, 3H). Retention time 5.34 minutes (Analytical SFCconditions identical to those used for 17).

The compounds listed in Table 1 were prepared using procedures analogousto the examples identified in Table 2 using the appropriateintermediate(s) identified in Table 2. The compounds were purified usingmethods discussed herein. The final compounds may have been isolated asneutrals or acid or base salts.

TABLE 1 Structure and IUPAC name for Examples 19-102 Ex. No. StructureIUPAC Name 19

2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperazin-1-yl}methyl)-1-(2-methoxyethyl)-1H- benzimidazole-6-carboxylic acid,trifluoroacetate salt 20

2-({4-[2-(4-chloro-2-fluorophenyl)-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-(2-methoxyethyl)-1H-benzimidazole-6- carboxylic acid, ENT-X2,trifluoroacetate salt, [from C77; footnote 1 in Table 2] 21

2-({4-[2-(4-chloro-2-fluorophenyl)-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-(2-methoxyethyl)-1H-benzimidazole-6- carboxylic acid, ENT-X1,trifluoroacetate salt, [from C76; footnote 1 in Table 2] 22

1-(2-methoxyethyl)-2-{[4-(2-phenyl-1,3-benzodioxol-4-yl)piperazin-1-yl]methyl}- 1H-benzimidazole-6-carboxylicacid, ENT-X1, trifluoroacetate salt, [from P5] 23

1-(2-methoxyethyl)-2-{[4-(2-phenyl-1,3-benzodioxol-4-yl)piperazin-1-yl]methyl}- 1H-benzimidazole-6-carboxylicacid, ENT-X2, trifluoroacetate salt, [from P6] 24

2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-(2-methoxyethyl)-1H- benzimidazole-6-carboxylic acid,trifluoroacetate salt 25

2-{6-[2-(4-chloro-2-fluorophenyl)-2- methyl-1,3-benzodioxol-4-yl]-6-azaspiro[2.5]oct-1-yl}-1-(2- methoxyethyl)-1H-benzimidazole-6-carboxylic acid, DIAST-Z2, trifluoroacetate salt, [from P17 via C79;footnote 2 in Table 2] 26

2-{6-[2-(4-chloro-2-fluorophenyl)-2- methyl-1,3-benzodioxol-4-yl]-6-azaspiro[2.5]oct-1-yl}-1-(2- methoxyethyl)-1H-benzimidazole-6-carboxylic acid, DIAST-Z1, trifluoroacetate salt, [from P17 via C78;footnote 2 in Table 2] 27

2-({4-[2-(4-cyano-2-fluorophenyl)-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-(2-methoxyethyl)-1H-benzimidazole-6- carboxylic acid, trifluoroacetatesalt 28

1-(2-methoxyethyl)-2-[(4-{2-methyl-2-[3-(trifluoromethyl)phenyl]-1,3-benzodioxol- 4-yl}piperidin-1-yhmethyl]-1H-benzimidazole-6-carboxylic acid, formate salt 29

2-({4-[2-(4-ethylphenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-(2-methoxyethyl)-1H-benzimidazole-6- carboxylic acid, formate salt 30

2-({4-[2-(3-fluoro-4-methoxyphenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-(2-methoxyethyl)-1H- benzimidazole-6-carboxylic acid,formate salt 31

2-({4-[2-(3-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-(2-methoxyethyl)-1H-benzimidazole-6- carboxylic acid, formate salt 32

1-(2-methoxyethyl)-2-({4-[2-(4- methoxyphenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)- 1H-benzimidazole-6-carboxylicacid, formate salt 33

2-({4-[2-(4-chlorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-(2-methoxyethyl)-1H-benzimidazole-6- carboxylic acid, formate salt 34

2-({4-[2-(4-cyanophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-(2-methoxyethyl)-1H-benzimidazole-6- carboxylic acid 35

2-({4-[2-(2-fluoro-4-methoxyphenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-(2-methoxyethyl)-1H- benzimidazole-6-carboxylic acid,formate salt 36

1-(2-methoxyethyl)-2-({4-[2-methyl-2-(6-methylpyridin-2-yl)-1,3-benzodioxol-4- yl]piperidin-1-yl}methyl)-1H-benzimidazole-6-carboxylic acid, formate salt 37

1-(2-methoxyethyl)-2-({4-[2-(2- methoxyphenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)- 1H-benzimidazole-6-carboxylicacid 38

2-({4-[2-(4-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-(2-methoxyethyl)-1H-benzimidazole-6- carboxylic acid, formate salt 39

1-(2-methoxyethyl)-2-({4-[2-(3- methoxyphenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)- 1H-benzimidazole-6-carboxylicacid, formate salt 40

1-(2-methoxyethyl)-2-[(4-{2-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-benzodioxol-4-yl}piperidin-1-yl)methyl]-1H- benzimidazole-6-carboxylic acid, formatesalt 41

2-({4-[2-(3,4-difluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1- yl}methyl)-1-(2-methoxyethyl)-1H-benzimidazole-6-carboxylic acid 42

1-(2-methoxyethyl)-2-({4-[2-methyl-2-(6-methylpyridin-3-yl)-1,3-benzodioxol-4- yl]piperidin-1-yl}methyl)-1H-benzimidazole-6-carboxylic acid, formate salt 43

1-{2-[acetyl(methyhamino]ethyl}-2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)- 1H-benzimidazole-6-carboxylicacid 44

2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[2-(morpholin-4-yl)ethyl]-1H- benzimidazole-6-carboxylicacid 45

2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-(pyridin-2-ylmethyl)-1H- benzimidazole-6-carboxylic acid 46

2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[2-(2-oxo-1,3-oxazolidin-3-yl}ethyl]-1H-benzimidazole-6-carboxylic acid 47

2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[2-(dimethylsulfamoyhethyl]- 1H-benzimidazole-6-carboxylicacid 48

2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[2-(2-oxopyrrolidin-1-yl)ethyl]-1H-benzimidazole-6-carboxylic acid 49

1-[2-(acetylamino)ethyl]-2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)- 1H-benzimidazole-6-carboxylicacid 50

2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[2-(1H-imidazol-1-yl)ethyl]- 1H-benzimidazole-6-carboxylicacid 51

2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(1-ethyl-1H-imidazol-2- yl)methyl]-1H-benzimidazole-6-carboxylic acid 52

2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[2-(methylamino)-2- oxoethyl]-1H-benzimidazole-6-carboxylicacid 53

2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[2-(1H-pyrazol-1-yl)ethyl]- 1H-benzimidazole-6-carboxylicacid 54

2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[3-(1H-1,2,4-triazol-1-yl)propyl]-1H-benzimidazole-6-carboxylic acid 55

2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[2-(1-methyl-1H-imidazol-4-yl)ethyl]-1H-benzimidazole-6-carboxylic acid 56

2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-(tetrahydrofuran-3- ylmethyl)-1H-benzimidazole-6-carboxylicacid 57

2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(1-methyl-1H-1,2,4-triazol-5-yl)methyl]-1H-benzimidazole-6- carboxylic acid 58

2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-(1,3-oxazol-4-ylmethyl)-1H- benzimidazole-6-carboxylic acid59

2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[3-(dimethylamino)-3- oxopropyl]-1H-benzimidazole-6-carboxylic acid 60

2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[2-(1-methyl-1H-1,2,3-triazol-4-yl)ethyl]-1H-benzimidazole-6- carboxylic acid 61

2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-(tetrahydrofuran-3-yl)-1H- benzimidazole-6-carboxylic acid62

2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[2-(2-methyl-1H-imidazol-1-yl)ethyl]-1H-benzimidazole-6-carboxylic acid 63

2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(1-methyl-1H-1,2,3-triazol-4-yl)methyl]-1H-benzimidazole-6- carboxylic acid 64

2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2R)-tetrahydrofuran-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid 65

2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-(pyridin-3-ylmethyl)-1H- benzimidazole-6-carboxylic acid 66

2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[2-(dimethylamino)-2- oxoethyl]-1H-benzimidazole-6-carboxylacid 67

2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[2-(pyrrolidin-1-yl)ethyl-1H- benzimidazole-6-carboxylicacid 68

2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-{[3-(methoxymethyl)-1H-pyrazol-5-yl]methyl}-1H-benzimidazole- 6-carboxylic acid 69

2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-(1,3-oxazol-5-ylmethyl)-1H- benzimidazole-6-carboxylic acid70

2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-{[4-(2-methoxyethyl)-4H- 1,2,4-triazol-3-yl]methyl}-1H-benzimidazole-6-carboxylic acid 71

2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1- yl}methyl)-1-{2-[methyl(methylsulfonyl)amino]ethyl}-1H- benzimidazole-6-carboxylic acid72

2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1- yl}methyl)-1-[(1-hydroxycyclobutyl)methyl-1H- benzimidazole-6-carboxylic acid 73

2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-(1H-pyrazol-4-ylmethyl)-1H- benzimidazole-6-carboxylicacid, trifluoroacetate salt 74

2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[2-(1H-imidazol-2-yl)ethyl]- 1H-benzimidazole-6-carboxylicacid, trifluoroacetate salt 75

2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-(2-hydroxyethyl)-1H- benzimidazole-6-carboxylic acid 76

2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(1-ethyl-1H-1,2,3-triazol-5- yl)methy]-1H-benzimidazole-6-carboxylic acid 77

2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(1-methyl-1H-imidazol-4- yl}methyl]-1H-benzimidazole-6-carboxylic acid 78

2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(4-methyl-4H-1,2,4-triazol-3-yl)methyl]-1H-benzimidazole-6- carboxylic acid 79

2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-tetrahydrofuran-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid 80

2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-(1,3-oxazol-2-ylmethyl)-1H- benzimidazole-6-carboxylic acid81

2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-3-(1,3-oxazol-5-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid 82

1-(2-methoxyethyl)-2-{[4-(2-methyl-2-phenyl-1,3-benzodioxol-4-yl)piperidin-1- yl]methyl}-1H-benzimidazole-6-carboxylic acid, formate salt 83

2-({4-[2-(2-chloro-4-methoxyphenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-(2-methoxyethyl)-1H- benzimidazole-6-carboxylic acid,formate salt 84

1-(2-methoxyethyl)-2-({4-[2-methyl-2-(4-methylphenyl)-1,3-benzodioxol-4- yl]piperidin-1-yl}methyl)-1H-benzimidazole-6-carboxylic acid, formate salt 85

1-(2-methoxyethyl)-2-({4-[2-methyl-2-(3-methylphenyl)-1,3-benzodioxol-4- yl]piperidin-1-yl}methyl)-1H-benzimidazole-6-carboxylic acid, formate salt 86

2-({4-[2-(2-chlorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-(2-methoxyethyl)-1H-benzimidazole-6- carboxylic acid, formate salt 87

2-({4-[2-(3-cyanophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-(2-methoxyethyl)-1H-benzimidazole-6- carboxylic acid, formate salt 88

1-(2-methoxyethyl)-2-({4-[2-methyl-2-(2-methylphenyl)-1,3-benzodioxol-4- yl]piperidin-1-yl}methyl)-1H-benzimidazole-6-carboxylic acid, formate salt 89

1-(2-methoxyethyl)-2-({4-[2-methyl-2- (pyridin-2-yl)-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1H- benzimidazole-6-carboxylic acid, ENT- X2,trifluoroacetate salt [from C81; footnote 7 in Table 2] 90

1-(2-methoxyethyl)-2-({4-[2-methyl-2- (pyridin-2-yl)-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1H- benzimidazole-6-carboxylic acid, ENT- X1,trifluoroacetate salt [from C80; footnote 7 in Table 2] 91

ammonium 2-({4-[2-(5-chloropyridin-2- yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-(2- methoxyethyl)-1H-benzimidazole-6-carboxylate, ENT-X1 [from P8] 92

ammonium 2-({4-[2-(5-chloropyridin-2- yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-(2- methoxyethyl)-1H-benzimidazole-6-carboxylate, ENT-X2 [from P9] 93

ammonium 2-({4-[2-(5-cyanopyridin-2- yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-(2- methoxyethyl)-1H-benzimidazole-6-carboxylate, ENT-X1 [from P8] 94

ammonium 2-({4-[2-(5-cyanopyridin-2- yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-(2- methoxyethyl)-1H-benzimidazole-6-carboxylate, ENT-X2 [from P9] 95

2-({4-[2-(5-chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1- yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid, DIAST-X1 [from P8] 96

2-({4-[2-(4-chloro-2-fluorophenyl)-7- fluoro-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6- carboxylic acid, DIAST-1 [footnote 10 inTable 2] 97

2-({4-[2-(4-chloro-2-fluorophenyl)-7- fluoro-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6- carboxylic acid, DIAST-2 [footnote 10 inTable 2] 98

ammonium 2-({4-[2-(4-cyano-2- fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-(1,3-oxazol-2-ylmethyl)-1H-benzimidazole-6- carboxylate, ENT-X2 [from C83; footnote12 in Table 2] 99

ammonium 2-({4-[2-(4-cyano-2- fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-(1,3-oxazol-2-ylmethyl)-1H-benzimidazole-6- carboxylate, ENT-X1 [from C82; footnote12 in Table 2] 100

2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-7-fluoro-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid, hemicitrate salt [from P3]101

2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-1,3-benzodioxol-4-yl]piperidin-1- yl}methyl)-7-fluoro-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid, hemicitrate salt [fromC48] 102

2-({4-[2-(hydroxymethyl)-2-phenyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-(2-methoxyethyl)-1H-benzimidazole-6- carboxylic acid, trifluoroacetatesalt

TABLE 2 Method of preparation and physicochemical data for Examples19-102. ¹H NMR(400 MHz, methanol-d₄) δ; Mass spectrum, Ex. observed ionm/z [M + H]⁺ or HPLC retention time; Mass No. Method spectrum m/z [M +H]⁺ (unless otherwise indicated) 19 Examples 8.39 (br s, 1H), 8.08 (d, J= 8.5 Hz, 1H), 7.81 (d, J = 15 and 16; 8.6 Hz, 1H), 7.60 (dd, J = 8.3,8.3 Hz, 1H), 7.28 (dd, C4, P12 J = 10.9, 2.1 Hz, 1H), 7.22 (dd, J = 8.4,2.0 Hz, 1H), 6.83 (dd, J = 8.1, 8.1 Hz, 1H), 6.60 (d, J = 7.8 Hz, 1H),6.55 (d, J = 8.4 Hz, 1H), 4.73 (s, 2H), 4.66 (t, J = 4.9 Hz, 2H), 3.77(t, J = 4.8 Hz, 2H), 3.59-3.43 (m, 8H), 3.30 (s, 3H{circumflex over( )}{circumflex over ( )}), 2.05 (s, 3H); 581.0 20 Examples 8.34-8.31(m, 1H), 8.03 (dd, J = 8.5, 1.5 Hz, 1H), 4 and 5¹; 7.78 (d, J = 8.6 Hz,1H), 7.60 (dd, J = 8.0, 8.0 Hz, 1H), C43, P11 7.36 (dd, J = 10.2, 1.9Hz, 1H), 7.31 (dd, J = 8.4, 1.8 Hz, 1H), 7.25 (s, 1H), 6.90 (dd,component of ABC pattern, J = 8.9, 6.6 Hz, 1H), 6.86-6.80 (m, 2H), 4.79(s, 2H), 4.60 (br t, J = 4.8 Hz, 2H), 3.95-3.85 (m, 2H), 3.74 (dd, J =5.3, 4.2 Hz, 2H), 3.44-3.33 (m, 2H), 3.28 (s, 3H), 3.15-3.05 (m, 1H),2.37-2.12 (m, 4H); 566.0♦ 21 Examples 8.32 (dd, J = 1.6, 0.7 Hz, 1H),8.03 (dd, J = 8.5, 1.5 4 and 5¹; Hz, 1H), 7.78 (dd, J = 8.5, 0.7 Hz,1H), 7.60 (dd, J = C43, P11 8.1, 7.9 Hz, 1H), 7.36 (dd, J = 10.2, 2.0Hz, 1H), 7.31 (br dd, J = 8.3, 1.8 Hz, 1H), 7.25 (s, 1H), 6.90 (dd,component of ABC pattern, J = 8.8, 6.7 Hz, 1H), 6.87- 6.80 (m, 2H), 4.79(s, 2H), 4.60 (t, J = 4.8 Hz, 2H), 3.90 (br d, J = 12.3 Hz, 2H), 3.74(dd, J = 5.3, 4.2 Hz, 2H), 3.38 (br dd, J = 12.6, 12.5 Hz, 2H), 3.28 (s,3H), 3.10 (tt, J = 11.9, 4.0 Hz, 1H), 2.37-2.11 (m, 4H); 566.0♦ 22Examples 8.37 (d, J = 1.5 Hz, 1H), 8.07 (dd, J = 8.5, 1.5 Hz, 1H), 1 and2; 7.79 (d, J = 8.6 Hz, 1H), 7.60-7.54 (m, 2H), 7.50- P12, P5 7.42 (m,3H), 6.98 (s, 1H), 6.86 (dd, J = 8.1, 8.1 Hz, 1H), 6.61 (dd, J = 7.9,0.9 Hz, 1H), 6.59 (dd, J = 8.4, 0.9 Hz, 1H), 4.73 (s, 2H), 4.64 (t, J =4.8 Hz, 2H), 3.75 (dd, J = 5.4, 4.3 Hz, 2H), 3.61-3.44 (m, 8H), 3.28 (s,3H); 515.1 23 Examples 8.37 (br s, 1H), 8.07 (dd, J = 8.6, 1.5 Hz, 1H),7.79 (d, 1 and 2; J = 8.5 Hz, 1H), 7.61-7.54 (m, 2H), 7.51-7.42 (m, P12,P6 3H), 6.98 (s, 1H), 6.86 (dd, J = 8.2, 8.1 Hz, 1H), 6.61 (br d, J = 8Hz, 1H), 6.59 (br d, J = 8.5 Hz, 1H), 4.69 (s, 2H), 4.64 (t, J = 4.9 Hz,2H), 3.75 (t, J = 4.9 Hz, 2H), 3.59-3.43 (m, 8H), 3.29 (s, 3H); 515.1 24Examples 8.33 (dd, J = 1.5, 0.6 Hz, 1H), 8.03 (dd, J = 8.5, 1.5 4 and 5;Hz, 1H), 7.79 (dd, J = 8.5, 0.5 Hz, 1H), 7.62 (dd, J = C13, P11 8.4, 8.3Hz, 1H), 7.29 (dd, J = 10.9, 2.0 Hz, 1H), 7.22 (ddd, J = 8.4, 2.0, 0.7Hz, 1H), 6.88-6.82 (m, 1H), 6.82-6.76 (m, 2H), 4.83 (s, 2H), 4.63 (t, J= 4.8 Hz, 2H), 3.98-3.88 (m, 2H), 3.75 (dd, J = 5.3, 4.2 Hz, 2H),3.47-3.36 (m, 2H), 3.31 (s, 3H{circumflex over ( )}{circumflex over( )}), 3.10 (tt, J = 12.0, 4.1 Hz, 1H), 2.36-2.10 (m, 4H), 2.05 (d, J =1.0 Hz, 3H); 580.1♦ 25 Examples 8.51 (dd, J = 1.5, 0.7 Hz, 1H), 8.25(dd, J = 8.6, 1.4 15 and 162; Hz, 1H), 7.79 (dd, J = 8.6, 0.7 Hz, 1H),7.57 (dd, J = C4, P17 8.3, 8.3 Hz, 1H), 7.25 (dd, J = 10.8, 2.0 Hz, 1H),7.19 (ddd, J = 8.4, 2.0, 0.7 Hz, 1H), 6.80-6.73 (m, 1H), 6.55-6.50 (m,2H), 4.9-4.73 (m, 2H{circumflex over ( )}), 3.92-3.81 (m, 2H), 3.66-3.58(m, 1H), 3.41-3.3 (m, 1H{circumflex over ( )}{circumflex over ( )}),3.25 (s, 3H), 3.20-3.12 (m, 1H), 3.05-2.97 (m, 1H), 2.70-2.63 (m, 1H),2.27-2.17 (m, 1H), 2.01 (d, J = 1.0 Hz, 3H), 1.84-1.71 (m, 2H),1.67-1.58 (m, 2H), 1.31 (br d, J = 13 Hz, 1H); 592.3♦ 26 Examples8.53-8.50 (m, 1H), 8.26 (dd, J = 8.6, 1.4 Hz, 1H), 15 and 16²; 7.81 (d,J = 8.6 Hz, 1H), 7.55 (dd, J = 8.3, 8.2 Hz, 1H), C4, 7.16-7.08 (m, 2H),6.77 (dd, J = 8.3, 7.9 Hz, 1H), P17 6.52 (br d, J = 8.3 Hz, 1H), 6.51(br d, J = 7.7 Hz, 1H), 4.9-4.74 (m, 2H{circumflex over ( )}), 3.83 (t,J = 4.8 Hz, 2H), 3.68- 3.60 (m, 1H), 3.54-3.46 (m, 1H), 3.18-3.09 (m,1H), 3.14 (s, 3H), 3.09-3.01 (m, 1H), 2.69-2.62 (m, 1H), 2.31-2.21 (m,1H), 2.01 (br s, 3H), 1.78-1.69 (m, 2H), 1.63-1.52 (m, 2H), 1.33-1.25(m, 1H); 592.3♦ 27 Examples 8.32 (br s, 1H), 8.02 (dd, J = 8.5, 1.5 Hz,1H), 7.82- 4 and 53; 7.76 (m, 2H), 7.73 (br d, J = 10.0 Hz, 1H), 7.67(br d, P11 J = 8.0 Hz, 1H), 7.35 (s, 1H), 6.96-6.89 (m, 1H), 6.88- 6.83(m, 2H), 4.76 (s, 2H), 4.61 (t, J = 4.8 Hz, 2H), 3.87 (br d, J = 12.3Hz, 2H), 3.74 (t, J = 4.8 Hz, 2H), 3.39-3.3 (m, 2H{circumflex over( )}{circumflex over ( )}), 3.29 (s, 3H), 3.15-3.05 (m, 1H), 2.35-2.10(m, 4H); 557.1 28 Example 3.08 minutes⁴; 596 11; P14 29 Example 3.12minutes⁴; 556 11; P14 30 Example 2.90 minutes⁴; 576 11; P14 31 Example2.92 minutes⁴; 546 11; P14 32 Example 2.88 minutes⁴; 558 11; P14 33Example 3.04 minutes⁴; 562 11; P14 34 Example 2.99 minutes⁵; 553 11; P1435 Example 2.92 minutes⁴; 576 11; P14 36 Example 2.81 minutes⁵; 543 11;P14 37 Example 2.90 minutes⁴; 558 11; P14 38 Example 2.91 minutes⁴; 54611; P14 39 Example 2.89 minutes⁴; 558 11; P14 40 Example 3.11 minutes⁴;596 11; P14 41 Example 2.97 minutes⁴; 564 11; P14 42 Example 2.40minutes⁵; 543 11; P14 43 Example 2.70 minutes⁴; 621 12; P10 44 Example2.49 minutes⁴; 635 12; P10 45 Example 2.79 minutes⁴; 613 12; P10 46Example 2.71 minutes⁴; 635 12; P10 47 Example 2.85 minutes⁴; 657 12; P1048 Example 2.71 minutes⁴; 633 12; P10 49 Example 2.66 minutes⁴; 607 12;P10 50 Example 2.43 minutes⁴; 616 12; P10 51 Example 2.74 minutes⁴; 63012; P10 52 Example 2.73 minutes⁴; 593 12; P10 53 Example 2.79 minutes⁴;616 12; P10 54 Example 2.67 minutes⁴; 631 12; P10 55 Example 2.44minutes⁴; 630 12; P10 56 Example 2.77 minutes⁴; 606 12; P10 57 Example2.72 minutes⁴; 617 12; P10 58 Example 2.78 minutes⁴; 603 12; P10 59Example 2.82 minutes⁴; 621 12; P10 60 Example 2.74 minutes⁴; 631 12; P1061 Example 2.76 minutes⁴; 592 12; P10 62 Example 2.45 minutes⁴; 630 12;P10 63 Example 2.78 minutes⁴; 617 12; P10 64 Example 2.84 minutes⁴; 60612; P10 65 Example 2.56 minutes⁴; 613 12; P10 66 Example 2.75 minutes⁴;607 12; P10 67 Example 2.48 minutes⁴; 619 12; P10 68 Example 2.75minutes⁴; 646 12; P10 69 Example 2.73 minutes⁴; 603 12; P10 70 Example2.86 minutes⁵; 661 12; P10 71 Example 2.77 minutes⁴; 657 12; P10 72Example 2.79 minutes⁴; 606 12; P10 73 Example 2.70 minutes⁴; 602 12; P1074 Example 2.45 minutes⁴; 616 12; P10 75 Example 2.92 minutes⁴; 566 13;P10 76 Example 2.99 minutes⁴; 631 13; P10 77 Example 2.94 minutes⁴; 61613; P10 78 Example 3.08 minutes⁵; 617 13; P10 79 Example 3.09 minutes⁴;606 13; P10 80 Example 3.02 minutes⁴; 603 13; P10 81 Example 3.10minutes⁵; 604 13; P10 82 Example 2.87 minutes⁴; 528 11; P14 83 Example3.00 minutes⁴; 592 11; P14 84 Example 2.99 minutes⁴; 542 11; P14 85Example 2.98 minutes⁴; 542 11; P14 86 Example 2.97 minutes⁴; 562 11; P1487 Example 2.97 minutes5; 553 11; P14 88 Example 2.90 minutes⁴; 542 11;P14 89 Examples 8.63 (ddd, J = 4.9, 1.8, 0.9 Hz, 1H), 8.34 (dd, J = 1.6,4 and 5^(6,7); 0.7 Hz, 1H), 8.03 (dd, J = 8.5, 1.5 Hz, 1H), 7.90 (ddd,P11 J = 7.8, 7.8, 1.7 Hz, 1H), 7.80 (dd, J = 8.5, 0.7 Hz, 1H), 7.74(ddd, J = 7.9, 1.1, 1.0 Hz, 1H), 7.45 (ddd, J = 7.6, 4.9, 1.2 Hz, 1H),6.88-6.83 (m, 1H), 6.83-6.76 (m, 2H), 4.83 (s, 2H), 4.63 (t, J = 4.8 Hz,2H), 3.99-3.88 (m, 2H), 3.75 (dd, J = 5.3, 4.2 Hz, 2H), 3.45-3.34 (m,2H), 3.31 (s, 3H), 3.15-3.03 (m, 1H), 2.41 −2.20 (m, 2H), 2.19-2.08 (m,2H), 2.05 (s, 3H); 529.3 90 Examples 8.63 (ddd, J = 4.9, 1.8, 0.9 Hz,1H), 8.34 (dd, J = 1.6, 4 and 5^(6,7); 0.7 Hz, 1H), 8.04 (dd, J = 8.5,1.5 Hz, 1H), 7.90 (ddd, P11 J = 7.8, 7.8, 1.7 Hz, 1H), 7.80 (dd, J =8.5, 0.7 Hz, 1H), 7.73 (ddd, J = 8.0, 1.1, 1.0 Hz, 1H), 7.45 (ddd, J =7.6, 4.9, 1.2 Hz, 1H), 6.88-6.83 (m, 1H), 6.83-6.75 (m, 2H), 4.83 (s,2H), 4.63 (t, J = 4.9 Hz, 2H), 3.98-3.88 (m, 2H), 3.75 (t, J = 4.8 Hz,2H), 3.44-3.34 (m, 2H), 3.32 (s, 3H{circumflex over ( )}{circumflex over( )}), 3.15-3.03 (m, 1H), 2.40-2.19 (m, 2H), 2.18-2.08 (m, 2H), 2.05 (s,3H); 529.3 91 Examples 8.59 (d, J = 2.4 Hz, 1H), 8.26 (d, J = 1.4 Hz,1H), 7.96 6 and 7; (dd, J = 8.5, 1.5 Hz, 1H), 7.87 (dd, J = 8.5, 2.5 Hz,1H), P8, P11 7.68-7.61 (m, 2H), 6.83-6.75 (m, 1H), 6.75-6.67 (m, 2H),4.67 (t, J = 5.2 Hz, 2H), 4.00 (s, 2H), 3.82 (t, J = 5.1 Hz, 2H), 3.29(s, 3H), 3.13-3.05 (m, 2H), 2.81- 2.70 (m, 1H), 2.45-2.34 (m, 2H), 2.01(s, 3H), 1.98- 1.77 (m, 4H); 563.3♦ 92 Examples 8.59 (d, J = 2.3 Hz,1H), 8.26 (d, J = 1.4 Hz, 1H), 7.96 6 and 7; (dd, J = 8.5, 1.5 Hz, 1H),7.87 (dd, J = 8.5, 2.5 Hz, 1H), P9, P11 7.68-7.62 (m, 2H), 6.82-6.76 (m,1H), 6.74-6.68 (m, 2H), 4.67 (t, J = 5.2 Hz, 2H), 4.00 (s, 2H), 3.82 (t,J = 5.1 Hz, 2H), 3.29 (s, 3H), 3.13-3.04 (m, 2H), 2.76 (tt, J = 11.8, 4Hz, 1H), 2.45-2.34 (m, 2H), 2.01 (s, 3H), 1.97-1.78 (m, 4H); 563.3♦ 93Examples 8.97 (dd, J = 2.1, 0.9 Hz, 1H), 8.27-8.25 (m, 1H), 8 and 9⁸;8.21 (dd, J = 8.2, 2.1 Hz, 1H), 7.96 (dd, J = 8.5, 1.5 P8, P11 Hz, 1H),7.81 (dd, J = 8.3, 0.9 Hz, 1H), 7.64 (d, J = 8.6 Hz, 1H), 6.83-6.77 (m,1H), 6.76-6.68 (m, 2H), 4.68 (t, J = 5.2 Hz, 2H), 3.95 (s, 2H), 3.83 (t,J = 5.2 Hz, 2H), 3.30 (s, 3H), 3.08-2.99 (m, 2H), 2.79-2.69 (m, 1H),2.39-2.28 (m, 2H), 2.04 (s, 3H), 1.96-1.76 (m, 4H); 554.4 94 Examples8.97 (dd, J = 2.2, 0.9 Hz, 1H), 8.26 (br s, 1H), 8.21 (dd, 8 and 9⁸; J =8.2, 2.1 Hz, 1H), 7.96 (dd, J = 8.4, 1.4 Hz, 1H), P9, P11 7.81 (dd, J =8.2, 0.9 Hz, 1H), 7.64 (br d, J = 8.5 Hz, 1H), 6.83-6.77 (m, 1H),6.76-6.69 (m, 2H), 4.68 (t, J = 5.3 Hz, 2H), 3.95 (s, 2H), 3.83 (t, J =5.2 Hz, 2H), 3.30 (s, 3H), 3.08-2.99 (m, 2H), 2.79-2.69 (m, 1H),2.39-2.28 (m, 2H), 2.04 (s, 3H), 1.96-1.76 (m, 4H); 554.4 95 Example8.61 (dd, J = 2.5, 0.7 Hz, 1H), 8.41 (s, 1H), 8.33 (dd, 10; P8, J = 1.6,0.7 Hz, 1H), 7.97 (dd, J = 8.5, 1.5 Hz, 1H), 7.88 P15 (dd, J = 8.5, 2.5Hz, 1H), 7.66 (dd, J = 8.5, 0.6 Hz, 1H), 7.65 (dd, J = 8.5, 0.7 Hz, 1H),6.82-6.77 (m, 1H), 6.76-6.69 (m, 2H), 5.32-5.24 (m, 1H), 4.9-4.83 (m,1H{circumflex over ( )}), 4.71 (dd, J = 15.4, 2.6 Hz, 1H), 4.65-4.58 (m,1H), 4.48 (ddd, J = 9.2, 6.0, 5.9 Hz, 1H), 4.03 (AB quartet, J_(AB) =13.9 Hz, Δν_(AB) = 49.7 Hz, 2H), 3.18- 3.11 (m, 1H), 3.06-2.98 (m, 1H),2.87-2.69 (m, 2H), 2.60-2.49 (m, 1H), 2.46-2.31 (m, 2H), 2.02 (s, 3H),1.98-1.79 (m, 4H); 574.9♦ 96 Examples 7.01 minutes¹¹; 610.5♦ 6 and7^(9,10); P15 97 Examples 7.89 minutes¹¹; 610.5♦ 6 and 7^(9,10); P15 98C54¹² 8.25-8.23 (m, 1H), 8.00 (dd, J = 8.5, 1.5 Hz, 1H), 7.89 (d, J =0.9 Hz, 1H), 7.76 (dd, J = 7.9, 7.6 Hz, 1H), 7.70 (d, J = 8.5 Hz, 1H),7.64 (dd, J = 10.6, 1.5 Hz, 1H), 7.57 (dd, J = 8.0, 1.5 Hz, 1H), 7.14(d, J = 0.9 Hz, 1H), 6.78 (dd, component of ABC pattern, J = 7.9, 7.8Hz, 1H), 6.70 (dd, component of ABC pattern, J = 7.8, 1.2 Hz, 1H), 6.66(br d, component of ABC pattern, J = 7.9 Hz, 1H), 5.94 (AB quartet,J_(AB) = 17.2 Hz, Δν_(AB) = 6.5 Hz, 2H), 3.96 (s, 2H), 3.02-2.92 (m,2H), 2.74- 2.63 (m, 1H), 2.31-2.21 (m, 2H), 2.05 (br s, 3H), 1.80- 1.58(m, 4H); 594.3 99 C54¹² 8.23 (d, J = 1.4 Hz, 1H), 8.00 (dd, J = 8.5, 1.5Hz, 1H), 7.89 (d, J = 0.9 Hz, 1H), 7.76 (dd, J = 7.9, 7.6 Hz, 1H), 7.69(d, J = 8.5 Hz, 1H), 7.64 (dd, J = 10.6, 1.5 Hz, 1H), 7.57 (dd, J = 8.1,1.5 Hz, 1H), 7.14 (d, J = 0.9 Hz, 1H), 6.78 (dd, component of ABCpattern, J = 7.8, 7.8 Hz, 1H), 6.70 (dd, component of ABC pattern, J =7.8, 1.2 Hz, 1H), 6.66 (br d, component of ABC pattern, J = 7.9 Hz, 1H),5.94 (AB quartet, J_(AB) = 17.1 Hz, Δν_(AB) = 6.6 Hz, 2H), 3.96 (s, 2H),3.01-2.92 (m, 2H), 2.74- 2.63 (m, 1H), 2.30-2.20 (m, 2H), 2.05 (br s,3H), 1.80- 1.58 (m, 4H); 594.3 100 Example characteristic peaks: 7.80(dd, J = 8.5, 6.6 Hz, 1H), 7, free 7.59 (dd, J = 8.3, 8.3 Hz, 1H), 7.51(d, J = 8.6 Hz, 1H), acid¹³; P3, 7.28 (dd, J = 10.9, 2.0 Hz, 1H), 7.21(br dd, J = 8.4, 2.0 C29 Hz, 1H), 6.83-6.77 (m, 1H), 6.76-6.71 (m, 2H),5.32- 5.23 (m, 1H), 4.99 (dd, J = 15.5, 7.1 Hz, 1H), 4.79 (dd, J = 15.6,2.8 Hz, 1H), 4.72-4.63 (m, 1H), 4.47 (ddd, J = 9.1, 6.0, 6.0 Hz, 1H),4.31 (AB quartet, J_(AB) = 14.4 Hz, Δν_(AB) = 33.3 Hz, 2H), 3.40 (br d,J = 11.9 Hz, 1H), 2.92-2.65 (m, 4H), 2.82 (AB quartet, J_(AB) = = 15.5Hz, Δν_(AB) = 37.5 Hz, 2H), 2.61-2.49 (m, 1H), 2.13- 1.87 (m, 4H), 2.04(s, 3H); 610.0♦ 101 Example characteristic peaks: 7.79 (dd, J = 8.5, 6.6Hz, 1H), 5, free 7.57 (dd, J = 8.0, 8.0 Hz, 1H), 7.49 (d, J = 8.5 Hz,1H), acid¹³; 7.35 (dd, J = 10.2, 1.9 Hz, 1H), 7.30 (br d, J = 8.4 Hz,C48, C29 1H), 7.22 (s, 1H), 6.88-6.82 (m, 1H), 6.82-6.74 (m, 2H),5.30-5.21 (m, 1H), 4.95 (dd, J = 15.4, 7.1 Hz, 1H), 4.77 (br d, J = 15.1Hz, 1H), 4.67-4.59 (m, 1H), 4.44 (ddd, J = 9.1, 5.9, 5.9 Hz, 1H), 4.28(AB quartet, J_(AB) = 14.4 Hz, Δν_(AB) = 31.7 Hz, 2H), 3.37 (br d, J =12.3 Hz, 1H{circumflex over ( )}{circumflex over ( )}), 2.92-2.61 (m,4H), 2.82 (AB quartet, J_(AB) = 15.6 Hz, Δν_(AB) = 37.1 Hz, 2H),2.58-2.47 (m, 1H), 2.12- 1.89 (m, 4H); 596.1♦ 102 Examples 8.34 (dd, J =1.6, 0.7 Hz, 1H), 8.04 (dd, J = 8.5, 1.5 4 and 5¹⁴; Hz, 1H), 7.80 (dd, J= 8.5, 0.7 Hz, 1H), 7.66-7.60 (m, P11 2H), 7.46-7.36 (m, 3H), 6.84-6.76(m, 2H), 6.74 (dd, J = 7.2, 2.0 Hz, 1H), 4.84 (s, 2H), 4.63 (t, J = 4.7Hz, 2H), 4.01-3.91 (m, 4H), 3.76 (dd, J = 5.3, 4.2 Hz, 2H), 3.47-3.37(m, 2H), 3.32 (s, 3H), 3.19-3.08 (m, 1H), 2.41-2.26 (m, 2H), 2.26-2.13(m, 2H); 544.2 {circumflex over ( )}area is assumed, peak is partiallyobscured by water peak {circumflex over ( )}{circumflex over ( )}area isassumed, peak is partially obscured by solvent peak ♦chlorine isotopepattern observed1. The racemic methyl ester [methyl2-({4-[2-(4-chloro-2-fluorophenyl)-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-(2-methoxyethyl)-1H-benzimidazole-6-carboxylate]was separated into its component enantiomers via SFC [Column: ChiralTechnologies ChiralCel OD-H, 5 μm; Mobile phase: 7:3 carbondioxide/(2-propanol containing 0.1% ammonium hydroxide)]. Thefirst-eluting enantiomer, ENT-1 (C76), was used in the synthesis ofExample 21, and the second-eluting enantiomer, ENT-2 (C77), wasconverted to Example 20. C76 retention time: 5.72 minutes (Column:Chiral Technologies Chiralpak OD-3, 4.6×150 mm, 3 μm; Mobile phase A:carbon dioxide; Mobile phase B: 2-propanol containing 0.05%diethylamine; Gradient: 5% to 40% B over 5.5 minutes, then held at 40% Bfor 3.0 minutes; Flow rate: 2.5 mL/minute). C77 retention time: 6.01minutes (Analytical SFC conditions identical to those used for C76).2. The methyl ester (methyl2-{6-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]-6-azaspiro[2.5]oct-1-yl}-1-(2-methoxyethyl)-1H-benzimidazole-6-carboxylate)derived from coupling of C4 and P17 was separated into its componentstereoisomers at the dioxolane via SFC [Column: Chiral TechnologiesChiralpak AD, 10 μm; Mobile phase: 65:35 carbon dioxide/(ethanolcontaining 0.1% ammonium hydroxide)]. The first-eluting isomer, DIAST-1(C78), was converted to Example 26; by examination of ¹H NMR data, thismaterial was the enantiomer of Example 15. The second-eluting isomer,DIAST-2 (C79), was used in the synthesis of Example 25; by examinationof ¹H NMR data, this material was the enantiomer of Example 16. C78retention time: 3.60 minutes (Column: Chiral Technologies ChiralpakAD-3, 4.6×100 mm, 3 μm; Mobile phase A: carbon dioxide; Mobile phase B:ethanol containing 0.05% diethylamine; Gradient: 5% to 40% B over 4.5minutes, then held at 40% B for 2.5 minutes; Flow rate: 2.8 mL/minute).C79 retention time: 3.82 minutes (Analytical SFC conditions identical tothose used for C78).3. 4-(4-Bromo-1,3-benzodioxol-2-yl)-3-fluorobenzonitrile was preparedvia treatment of 3-fluoro-4-formylbenzonitrile and3-bromobenzene-1,2-diol with p-toluenesulfonic acid in toluene, withremoval of water using a Dean-Stark apparatus. This material was thenreacted with [1-(tert-butoxycarbonyl)piperidin-4-yl](iodo)zinc in thepresence of [1,1′-bis(diphenylphosphino)ferro-cene]dichloropalladium(II)and copper(i) iodide, followed by ester cleavage usingp-toluene-sulfonic acid, to afford the requisite3-fluoro-4-[4-(piperidin-4-yl)-1,3-benzodioxol-2-yl]benzonitrile.4. Conditions for analytical HPLC. Column: Waters XBridge C18, 2.1×50mm, 5 μm; Mobile phase A: 0.0375% trifluoroacetic acid in water; Mobilephase B: 0.01875% trifluoroacetic acid in acetonitrile; Gradient: 10% to100% B over 4.0 minutes; Flow rate: 0.8 mL/minute.5. Conditions for analytical HPLC. Column: Waters XBridge C18, 2.1×50mm, 5 μm; Mobile phase A: 0.0375% trifluoroacetic acid in water; Mobilephase B: 0.01875% trifluoroacetic acid in acetonitrile; Gradient: 1% to5% B over 0.6 minutes; 5% to 100% B over 3.4 minutes; Flow rate: 0.8mL/minute.6. tert-Butyl4-[2-methyl-2-(pyridin-2-yl)-1,3-benzodioxol-4-yl]-3,6-dihydropyridine-1(2H)-carboxylatewas synthesized from 3-bromobenzene-1,2-diol and 2-ethynylpyridine usingthe procedure described for synthesis of C12 in Preparation P7.Subsequent hydrogenation over palladium on carbon, followed by treatmentwith hydrogen chloride in ethyl acetate, afforded the requisite2-[2-methyl-4-(piperidin-4-yl)-1,3-benzodioxol-2-yl]pyridine,hydrochloride salt.7. The racemic methyl ester [methyl1-(2-methoxyethyl)-2-({4-[2-methyl-2-(pyridin-2-yl)-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1H-benzimidazole-6-carboxylate]was separated into its component enantiomers via SFC [Column: ChiralTechnologies Chiralpak AD, 10 μm; Mobile phase: 65:35 carbondioxide/(ethanol containing 0.1% ammonium hydroxide)]. The first-elutingenantiomer ENT-1 (C80) was used in the synthesis of Example 90, and thesecond-eluting enantiomer ENT-2 (C81) was converted to Example 89. C80retention time: 4.11 minutes (Column: Chiral Technologies ChiralpakAD-3, 4.6×100 mm, 3 μm; Mobile phase A: carbon dioxide; Mobile phase B:ethanol containing 0.05% diethylamine; Gradient: 5% to 40% B over 4.5minutes, then held at 40% B for 2.5 minutes; Flow rate: 2.8 mL/minute).C81 retention time: 4.62 minutes (Analytical SFC conditions identical tothose used for C80).8. Conversion of P8 and P9 to the corresponding cyano-substitutedderivatives was carried out using the method described for synthesis ofP4 from P2 in Preparation P4.9. Treatment of 1-(4-chloro-2-fluorophenyl)ethanone with trimethylorthoformate and p-toluene-sulfonic acid provided4-chloro-1-(1,1-dimethoxyethyl)-2-fluorobenzene, which was reacted with3-bromo-6-fluorobenzene-1,2-diol in the presence of p-toluenesulfonicacid to afford4-bromo-2-(4-chloro-2-fluorophenyl)-7-fluoro-2-methyl-1,3-benzodioxole.This material was converted to the requisite tert-butyl4-[2-(4-chloro-2-fluorophenyl)-7-fluoro-2-methyl-1,3-benzodioxol-4-yl]piperidine-1-carboxylateusing the method described in Preparation P1 for synthesis of P1 fromC2.10. Separation of the stereoisomers at the dioxolane in 96 and 97 wascarried out using SFC [Column: Chiral Technologies Chiralpak IG, 5 μm;Mobile phase: 3:1 carbon dioxide/(2-propanol containing 0.2% ammoniumhydroxide)]. The first-eluting isomer was designated as DIAST-1 (96) andthe second-eluting isomer as DIAST-2 (97).11. Conditions for analytical SFC. Column: Chiral Technologies ChiralpakIG, 4.6×100 mm, 5 μm; Mobile phase: 7:3 carbon dioxide/(2-propanolcontaining 0.2% ammonium hydroxide); Flow rate: 1.5 mL/minute; Backpressure: 150 bar.12. tert-Butyl2-(chloromethyl)-1-(1,3-oxazol-2-ylmethyl)-1H-benzimidazole-6-carboxylatewas synthesized from tert-butyl 3-fluoro-4-nitrobenzoate and1-(1,3-oxazol-2-yl)methanamine, using the method described for synthesisof P11. Subsequent reaction with C54 was carried out using triethylamineto afford tert-butyl2-({4-[2-(4-cyano-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-(1,3-oxazol-2-ylmethyl)-1H-benzimidazole-6-carboxylate,which was separated into its component enantiomers using SFC [Column:Chiral Technologies ChiralCel OD-H, 5 μm; Mobile phase: 55:45 carbondioxide/(ethanol containing 0.1% ammonium hydroxide)]. The first-elutingenantiomer ENT-1 (C82) was used in the synthesis of 99, and thesecond-eluting enantiomer ENT-2 (C83) was converted to 98. C82 retentiontime: 1.47 minutes (Column: Chiral Technologies Chiralpak OD-3, 4.6×50mm, 3 μm; Mobile phase A: carbon dioxide; Mobile phase B: methanolcontaining 0.05% diethylamine; Gradient: 5% B for 0.2 minutes, then 5%to 40% B over 1.4 minutes, then held at 40% B for 1.05 minutes; Flowrate: 4 mL/minute). C83 retention time: 1.85 minutes (Analytical SFCconditions identical to those used for C82).13. Reaction of 1-bromo-2,3-difluoro-4-nitrobenzene with copper(I)cyanide in 1-methylpyrrolidin-2-one at elevated temperature provided2,3-difluoro-4-nitrobenzonitrile, which was subjected to thionylchloride and methanol to afford methyl 2,3-difluoro-4-nitrobenzoate.This material was converted, through use of C29, to the requisite methyl2-(chloromethyl)-7-fluoro-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylate,via the method described in Preparation P11 for synthesis of P11 frommethyl 3-fluoro-4-nitrobenzoate.14. The requisite[2-phenyl-4-(piperidin-4-yl)-1,3-benzodioxol-2-yl]methanol wassynthesized from 2-oxo-2-phenylethyl acetate, by analogy to the methoddescribed for synthesis of C13.

CHO GLP-1R Clone H6—Assay 1

GLP-1R-mediated agonist activity was determined with a cell-basedfunctional assay utilizing an HTRF (Homogeneous Time-ResolvedFluorescence) cAMP detection kit (cAMP HI Range Assay Kit; CisBio cat#62AM6PEJ) that measures cAMP levels in the cell. The method is acompetitive immunoassay between native cAMP produced by the cells andexogenous cAMP labeled with the dye d2. The tracer binding is visualizedby a mAb anti-cAMP labeled with Cryptate. The specific signal (i.e.energy transfer) is inversely proportional to the concentration of cAMPin either standard or experimental sample.

The human GLP-1R coding sequence (NCBI Reference Sequence NP_002053.3,including naturally-occurring variant Gly168Ser) was subcloned intopcDNA3 (Invitrogen) and a cell line stably expressing the receptor wasisolated (designated Clone H6). Saturation binding analyses (filtrationassay procedure) using ¹²⁵I-GLP-1₇₋₃₆ (Perkin Elmer) showed that plasmamembranes derived from this cell line express a high GLP-1R density(K_(d): 0.4 nM, B_(max): 1900 fmol/mg protein).

Cells were removed from cryopreservation, re-suspended in 40 mL ofDulbecco's Phosphate Buffered Saline (DPBS—Lonza Cat #17-512Q) andcentrifuged at 800×g for 5 minutes at 22° C. The cell pellet was thenre-suspended in 10 mL of growth medium [DMEM/F12 1:1 Mixture with HEPES,L-Gln, 500 mL (DMEM/F12 Lonza Cat #12-719F), 10% heat inactivated fetalbovine serum (Gibco Cat #16140-071), 5 mL of 100× Pen-Strep (Gibco Cat#15140-122), 5 mL of 100×L-Glutamine (Gibco Cat #25030-081) and 500μg/mL Geneticin (G418) (Invitrogen #10131035)]. A 1 mL sample of thecell suspension in growth media was counted on a Becton Dickinson ViCellto determine cell viability and cell count per mL. The remaining cellsuspension was then adjusted with growth media to deliver 2000 viablecells per well using a Matrix Combi Multidrop reagent dispenser, and thecells were dispensed into a white 384 well tissue culture treated assayplate (Corning 3570). The assay plate was then incubated for 48 hours at37° C. in a humidified environment in 5% carbon dioxide.

Varying concentrations of each compound to be tested (in DMSO) werediluted in assay buffer (HBSS with Calcium/Magnesium (Lonza/BioWhittakercat #10-527F)/0.1% BSA (Sigma Aldrich cat #A7409-1L)/20 mM HEPES(Lonza/BioWhittaker cat #17-737E) containing 100 μM3-isobutyl-1-methylxanthin (IBMX; Sigma cat #15879). The final DMSOconcentration is 1%.

After 48 hours, the growth media was removed from the assay plate wells,and the cells were treated with 20 μL of the serially diluted compoundin assay buffer for 30 minutes at 37° C. in a humidified environment in5% carbon dioxide. Following the 30 minute incubation, 10 μL of labeledd2 cAMP and 10 μL of anti-cAMP antibody (both diluted 1:20 in cell lysisbuffer; as described in the manufacturer's assay protocol) were added toeach well of the assay plate. The plates were then incubated at roomtemperature and after 60 minutes, changes in the HTRF signal were readwith an Envision 2104 multi-label plate reader using excitation of 330nm and emissions of 615 and 665 nm. Raw data were converted to nM cAMPby interpolation from a cAMP standard curve (as described in themanufacturer's assay protocol) and the percent effect was determinedrelative to a saturating concentration of the full agonist GLP-1₇₋₃₆ (1μM) included on each plate. EC₅₀ determinations were made from agonistdose-response curves analyzed with a curve fitting program using a4-parameter logistic dose response equation.

CHO GLP-1R Clone C6—Assay 2

GLP-1R-mediated agonist activity was determined with a cell-basedfunctional assay utilizing an HTRF (Homogeneous Time-ResolvedFluorescence) cAMP detection kit (cAMP HI Range Assay Kit; Cis Bio cat#62AM6PEJ) that measures cAMP levels in the cell. The method is acompetitive immunoassay between native cAMP produced by the cells andexogenous cAMP labeled with the dye d2. The tracer binding is visualizedby a mAb anti-cAMP labeled with Cryptate. The specific signal (i.e.energy transfer) is inversely proportional to the concentration of cAMPin either a standard or an experimental sample.

The human GLP-1R coding sequence (NCBI Reference Sequence NP_002053.3,including naturally-occurring variant Leu260Phe) was subcloned intopcDNA5-FRT-TO and a clonal CHO cell line stably expressing a lowreceptor density was isolated using the Flp-In™ T-Rex™ System, asdescribed by the manufacturer (ThermoFisher). Saturation bindinganalyses (filtration assay procedure) using ¹²⁵I-GLP-1 (Perkin Elmer)showed that plasma membranes derived from this cell line (designatedclone C6) express a low GLP-1R density (K_(d): 0.3 nM, B_(max): 240fmol/mg protein), relative to the clone H6 cell line.

Cells were removed from cryopreservation, re-suspended in 40 mL ofDulbecco's Phosphate Buffered Saline (DPBS—Lonza Cat #17-512Q) andcentrifuged at 800×g for 5 minutes at 22° C. The DPBS was aspirated, andthe cell pellet was re-suspended in 10 mL of complete growth medium(DMEM:F12 1:1 Mixture with HEPES, L-Gln, 500 mL (DMEM/F12 Lonza Cat#12-719F), 10% heat inactivated fetal bovine serum (Gibco Cat#16140-071), 5 mL of 100× Pen-Strep (Gibco Cat #15140-122), 5 mL of100×L-Glutamine (Gibco Cat #25030-081), 700 μg/mL Hygromycin (InvitrogenCat #10687010) and 15 μg/mL Blasticidin (Gibco Cat #R21001). A 1 mLsample of the cell suspension in growth media was counted on a BectonDickinson ViCell to determine cell viability and cell count per mL. Theremaining cell suspension was then adjusted with growth media to deliver1600 viable cells per well using a Matrix Combi Multidrop reagentdispenser, and the cells were dispensed into a white 384 well tissueculture treated assay plate (Corning 3570). The assay plate was thenincubated for 48 hours at 37° C. in a humidified environment (95% O₂, 5%CO₂)

Varying concentrations of each compound to be tested (in DMSO) werediluted in assay buffer [HBSS with Calcium/Magnesium (Lonza/BioWhittakercat #10-527F)/0.1% BSA (Sigma Aldrich cat #A7409-1L)/20 mM HEPES(Lonza/BioWhittaker cat #17-737E)] containing 100 μM3-isobutyl-1-methylxanthin (IBMX; Sigma cat #15879). The final DMSOconcentration in the compound/assay buffer mixture is 1%.

After 48 hours, the growth media was removed from the assay plate wells,and the cells were treated with 20 μL of the serially diluted compoundin assay buffer for 30 minutes at 37° C. in a humidified environment(95% O₂, 5% CO₂). Following the 30 minute incubation, 10 μL of labeledd2 cAMP and 10 μL of anti-cAMP antibody (both diluted 1:20 in cell lysisbuffer; as described in the manufacturer's assay protocol) were added toeach well of the assay plate. The plates were then incubated at roomtemperature and after 60 minutes, changes in the HTRF signal were readwith an Envision 2104 multi-label plate reader using excitation of 330nm and emissions of 615 and 665 nm. Raw data were converted to nM cAMPby interpolation from a cAMP standard curve (as described in themanufacturer's assay protocol) and the percent effect was determinedrelative to a saturating concentration of the full agonist GLP-1 (1 μM)included on each plate. EC₅₀ determinations were made from agonist doseresponse curves analyzed with a curve fitting program using a4-parameter logistic dose response equation.

In Table 3, assay data are presented to two (2) significant figures asthe geometric mean (EC₅₀s) and arithmetic mean (Emax) based on thenumber of replicates listed (Number). A blank cell means there was nodata for that Example or the Emax was not calculated.

TABLE 3 Biological activity for Examples 1-102. Assay 1 Assay 1 Assay 1Assay 2 Assay 2 Assay 2 Ex. No. EC₅₀ (nM) Emax (%) Number EC₅₀ (nM) Emax(%) Number  1 880 99 3 >20000 1  2* 6.6 81 5 260 100 4  3 1.3 94 3 45120 3  4 1600 87 3 >20000 1   5** 1.3 89 6 23 97 7  6 140 89 7 2400 89 5  7** 0.26 98 3 3.1 93 12   8*** 0.30 92 6 3.6 91 6   9*** 73 88 9 160090 4   10**** 0.96 99 5 17 96 8 11 290 78 3 12 29 83 3 690 92 3 13 4.595 3 38 110 3 14 7 95 6 79 85 5 15 >18000 100 3 >20000 1 16 7.7 90 3 12064 3 17 0.079 97 3 1.1 96 4 18 210 97 3 1000 87 3 19 1.2 87 3 25 100 320 17 85 3 270 100 3 21 >20000 1 >20000 1 22 >20000 1 23 680 76 3 24 1.482 3 49 110 3 25 >20000 1 >20000 1 26 >20000 1 >20000 1 27 61 98 3 1000100 3 28 480 87 3 29 5.3 87 4 150 93 3 30 45 86 4 1100 77 4 31 190 88 31900 65 3 32 18 86 3 450 87 3 33 2.6 85 3 100 86 3 34 7.8 98 3 110 88 335 6.6 86 3 170 89 3 36 760 85 3 37 81 100 3 1000 83 3 38 10 87 3 240 733 39 200 83 3 40 14 88 3 130 73 3 41 91 78 3 2000 74 2 42 120 93 3 170083 3 43 3.5 88 4 65 86 3 44 160 78 4 45 9.9 81 3 220 79 3 46 5.2 95 4 5796 3 47 42 75 3 1400 76 4 48 14 81 3 280 73 3 49 230 93 3 50 12 87 4 14092 4 51 19 80 3 280 81 3 52 32 85 3 570 80 3 53 3.1 87 3 52 84 4 54 1882 3 160 64 3 55 74 81 3 1100 50 3 56 1.2 87 4 11 81 3 57 15 86 3 500 983 58 4 98 3 23 88 4 59 74 85 3 680 53 3 60 15 82 3 240 60 3 61 10 79 3240 85 3 62 2.2 94 3 82 95 3 63 5.2 91 3 66 96 3 64 9.2 94 3 91 80 3 651.2 99 3 11 99 6 66 51 82 3 850 74 3 67 710 83 3 68 73 89 3 1200 94 3 6910 100 3 8.3 98 3 70 2.8 100 4 97 100 4 71 6.8 80 4 74 80 3 72 14 76 3310 80 3 73 1.7 98 3 10 100 3 74 460 90 3 75 65 82 3 1000 71 3 76 0.7793 3 7.6 100 3 77 53 89 3 1700 92 3 78 4.5 89 4 78 100 3 79 1.4 85 3 2185 3 80 1.1 87 3 6.9 96 4 81 29 110 3 54 110 3 82 47 83 3 1000 83 3 833.4 85 4 44 88 4 84 9.1 93 3 100 86 3 85 230 80 3 86 24 91 3 410 100 387 570 89 3 88 17 86 3 360 91 3 89 130 85 3 2900 87 3 90 >20000 1 9114000 100 3 >20000 1 92 4.2 90 5 72 83 3 93 >6500 84 5 >20000 1 94 12 895 360 87 3   95**** 220 77 3 >13000 5 96 1.1 85 3 11 93 4 97 14 86 3 14093 4 98 50 97 3 440 95 3 99 2.8 99 4 5.4 91 2 100  7.6 99 1 101  19 74 1102  600 86 4 *Tested as ammonium and trifluoroacetate salts **Tested asammonium and 1,3-dihydroxy-2-(hydroxymethyl)propan-2-aminium (Tris)salts, and free acid ***Tested as ammonium salt and free acid ****Testedas formate salt and free acid

All patents, patent applications and references referred to herein arehereby incorporated by reference in their entirety.

What is claimed is:
 1. A method for treating a cardiometabolic andassociated disease or disorder comprising administering to a human inneed of such treatment a therapeutically effective amount of a compound,wherein the disease or disorder is selected from the group consisting ofT2DM, pre-diabetes, LADA, EOD, YOAD, MODY, malnutrition-relateddiabetes, gestational diabetes, hyperglycemia, insulin resistance,hepatic insulin resistance, impaired glucose tolerance, diabeticneuropathy, diabetic nephropathy, kidney disease, diabetic retinopathy,adipocyte dysfunction, visceral adipose deposition, obesity, eatingdisorders, weight gain from use of other agents, excessive sugarcraving, dyslipidemia, hyperinsulinemia, NAFLD, NASH, fibrosis, NASHwith fibrosis, cirrhosis, hepatocellular carcinoma, and metabolicsyndrome; and wherein the compound is2-({4-[2-(4-cyano-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylicacid;2-({4-[2-(5-chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylicacid;2-({4-[(2S)-2-(4-cyano-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylicacid;2-({4-[(2S)-2-(5-chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylicacid;2-({4-[(2R)-2-(4-cyano-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylicacid; or2-({4-[(2R)-2-(5-chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylicacid, or a pharmaceutically acceptable salt thereof.
 2. The method ofclaim 1 wherein the compound is2-({4-[2-(4-cyano-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylicacid;2-({4-[(2S)-2-(4-cyano-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylicacid; or2-({4-[(2R)-2-(5-chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylicacid, or a pharmaceutically acceptable salt thereof.
 3. The method ofclaim 2 wherein the compound is2-({4-[2-(4-cyano-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylicacid, or a pharmaceutically acceptable salt thereof.
 4. The method ofclaim 3 wherein the compound is a pharmaceutically acceptable salt of2-({4-[2-(4-cyano-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylicacid.
 5. A method for treating a cardiometabolic and associated diseaseor disorder comprising administering to a human in need of suchtreatment a therapeutically effective amount of a compound, wherein thedisease or disorder is selected from the group consisting of T2DM,pre-diabetes, malnutrition-related diabetes, gestational diabetes,hyperglycemia, insulin resistance, hepatic insulin resistance, impairedglucose tolerance, diabetic neuropathy, diabetic nephropathy, kidneydisease, diabetic retinopathy, adipocyte dysfunction, visceral adiposedeposition, obesity, eating disorders, weight gain from use of otheragents, excessive sugar craving, dyslipidemia, hyperinsulinemia, NAFLD,NASH, fibrosis, NASH with fibrosis, cirrhosis, hepatocellular carcinoma,and metabolic syndrome; and wherein the compound is2-({4-[2-(4-cyano-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylicacid, DIAST-X1; or2-({4-[2-(4-cyano-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylicacid, DIAST-X2, or a pharmaceutically acceptable salt thereof.
 6. Themethod of claim 5 wherein the compound is2-({4-[2-(4-cyano-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylicacid, DIAST-X1, or a pharmaceutically acceptable salt thereof.
 7. Themethod of claim 6 wherein the compound is a pharmaceutically acceptablesalt of2-({4-[2-(4-cyano-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylicacid, DIAST-X1.
 8. The method of claim 5 wherein the compound is2-({4-[2-(4-cyano-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylicacid, DIAST-X2, or a pharmaceutically acceptable salt thereof.
 9. Themethod of claim 8 wherein the compound is a pharmaceutically acceptablesalt of2-({4-[2-(4-cyano-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylicacid, DIAST-X2.
 10. A method for treating a cardiometabolic andassociated disease or disorder comprising administering to a human inneed of such treatment a therapeutically effective amount of a compound,wherein the disease or disorder is selected from the group consisting ofT2DM, pre-diabetes, malnutrition-related diabetes, gestational diabetes,hyperglycemia, insulin resistance, hepatic insulin resistance, impairedglucose tolerance, diabetic neuropathy, diabetic nephropathy, kidneydisease, diabetic retinopathy, adipocyte dysfunction, visceral adiposedeposition, obesity, eating disorders, weight gain from use of otheragents, excessive sugar craving, dyslipidemia, hyperinsulinemia, NAFLD,NASH, fibrosis, NASH with fibrosis, cirrhosis, hepatocellular carcinoma,and metabolic syndrome; and wherein the compound is2-({4-[2-(5-chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylicacid;2-({4-[(2S)-2-(5-chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylicacid; or2-({4-[(2R)-2-(5-chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylicacid, or a pharmaceutically acceptable salt thereof.
 11. The method ofclaim 10 wherein the compound is2-({4-[2-(5-chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylicacid or a pharmaceutically acceptable salt thereof.
 12. The method ofclaim 10 wherein the compound is a pharmaceutically acceptable salt of2-({4-[2-(5-chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylicacid.
 13. The method of claim 10 wherein the compound is2-({4-[2-(5-chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylicacid, DIAST-X1, or a pharmaceutically acceptable salt thereof.
 14. Themethod of claim 13 wherein the compound is2-({4-[2-(5-chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylicacid, DIAST-X1.
 15. The method of claim 13 wherein the compound is apharmaceutically acceptable salt of2-({4-[2-(5-chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylicacid, DIAST-X1.
 16. A method for treating a cardiometabolic andassociated disease or disorder comprising administering to a human inneed of such treatment a therapeutically effective amount of a compound,wherein the disease or disorder is selected from the group consisting ofT2DM, pre-diabetes, malnutrition-related diabetes, gestational diabetes,hyperglycemia, insulin resistance, hepatic insulin resistance, impairedglucose tolerance, diabetic neuropathy, diabetic nephropathy, kidneydisease, diabetic retinopathy, adipocyte dysfunction, visceral adiposedeposition, obesity, eating disorders, weight gain from use of otheragents, excessive sugar craving, dyslipidemia, hyperinsulinemia, NAFLD,NASH, fibrosis, NASH with fibrosis, cirrhosis, hepatocellular carcinoma,and metabolic syndrome; and wherein the compound is2-({4-[2-(5-chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylicacid, DIAST-X2, or a pharmaceutically acceptable salt thereof.
 17. Amethod for treating a cardiometabolic and associated disease or disordercomprising administering to a human in need of such treatment atherapeutically effective amount of a compound, wherein the disease ordisorder is selected from the group consisting of T2DM, pre-diabetes,malnutrition-related diabetes, gestational diabetes, hyperglycemia,insulin resistance, hepatic insulin resistance, impaired glucosetolerance, diabetic neuropathy, diabetic nephropathy, kidney disease,diabetic retinopathy, adipocyte dysfunction, visceral adiposedeposition, obesity, eating disorders, weight gain from use of otheragents, excessive sugar craving, dyslipidemia, hyperinsulinemia, NAFLD,NASH, fibrosis, NASH with fibrosis, cirrhosis, hepatocellular carcinoma,and metabolic syndrome; and wherein the compound is2-({4-[2-(5-chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylicacid, DIAST-X2.
 18. The method of claim 16 wherein the compound is apharmaceutically acceptable salt of2-({4-[2-(5-chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylicacid, DIAST-X2.
 19. The method of claim 18 wherein wherein thepharmaceutically acceptable salt is1,3-dihydroxy-2-(hydroxymethyl)propan-2-amine salt (tris salt).